Editorial

D

ear Colleagues,

The nervous system is made up of specific elements (neurons and glial cells) which are organized into networks. Each of these has its own particular activity, and its functions are coordinated by various regulatory systems. Some parts of the nervous system are characterized by their plasticity, and consequently their capacity to respond in an adaptive fashion to events (both positive and negative). These events can take the form either of an attack against the nerve cells (neurotoxicity) or of protection of these cells (neuroprotection). They may result from pathologies (depression, delusional syndromes, neurodegenerative diseases) or they may be linked to the action of either therapeutic agents (antidepressant medications with a neuroprotective action, for example) or to that of toxic agents (drug abuse). For a long time it was difficult to investigate neurotoxicity and neuroprotection, as there was a lack of specifically designed technologies for the examination of the microanatomy of the nervous system. Now, new methods of detailed microimaging and experimental protocols allowing their use have allowed us to observe the results of these processes. We are now able to obtain both qualitative and quantitative information on nerve cells, and to assess their functioning. It seemed an opportune moment to invite researchers in these particular areas to share their knowledge and to provide an update on the status of their research. There are now new models available to explain disorders of the nervous system and their treatment. Consequently, this is the focus we have chosen for this issue of Dialogues in Clinical Neuroscience. We warmly thank the brilliant authors who have lent their expertise to this issue, and naturally we also particularly thank our colleagues David Rubinow and Pierre Schulz, who agreed to coordinate it.

Sincerely yours,

Jean-Paul Macher, MD

233

Dialogues in Clinical Neuroscience is a quarterly publication that aims to serve as an interface between clinical neuropsychiatry and the neurosciences by providing state-of-the-art information and original insights into relevant clinical, biological, and therapeutic aspects. Each issue addresses a specific topic, and also publishes free contributions in the field of neuroscience as well as other non–topic-related material. All contributions are reviewed by members of the Editorial Board and submitted to expert consultants for peer review. Indexed in MEDLINE, Index Medicus, EMBASE, Scopus, Elsevier BIOBASE, and PASCAL/INIST-CNRS. EDITORIAL OFFICES Editor in Chief Jean-Paul MACHER, MD BP30 - F-68250 Rouffach - France Tel: + 33 3 89 49 56 60 / Fax: +33 3 89 49 56 74 Secretariat, subscriptions, and submission of manuscripts Marc-Antoine CROCQ, MD BP29 - F-68250 Rouffach - France Tel: +33 3 89 78 71 20 (direct) or +33 3 89 78 70 10 (secretariat) Fax: +33 3 89 78 72 00 / E-mail: ma.crocq@ch-rouffach.fr Annual subscription rates: Europe €150; Rest of World €170. Production Editor Catriona DONAGH, BAppSc Servier International - Medical Publishing Division 35 rue de Verdun 92284 Suresnes - France Tel: +33 1 55 72 32 79 / Fax: +33 1 55 72 58 84 E-mail: catriona.donagh@fr.netgrs.com PUBLISHER Les Laboratoires Servier 22 rue Garnier - 92578 Neuilly-sur-Seine Cedex - France E-mail: mail.dialneuro@fr.netgrs.com Copyright © 2009 by Les Laboratoires Servier All rights reserved throughout the world and in all languages. No part of this publication may be reproduced, transmitted, or stored in any form or by any means either mechanical or electronic, including photocopying, recording, or through an information storage and retrieval system, without the written permission of the copyright holder. Opinions expressed do not necessarily reflect the views of the publisher, editors, or editorial board. The authors, editors, and publisher cannot be held responsible for errors or for any consequences arising from the use of information contained in this journal. ISSN 1294-8322
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Contents
Page

233 237 239 257 269 281 297 305 319 333 350

Editorial
Jean-Paul Macher

In this issue
David R. Rubinow

State of the art
Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: stress and depression Ronald S. Duman (USA)

Translational research
Chromatin regulation in drug addiction and depression William Renthal, Eric J. Nestler (USA) Neuroplasticity of excitatory and inhibitory cortical circuits in schizophrenia David A. Lewis (USA) The role of astroglia in neuroprotection Mireille Bélanger, Pierre J. Magistretti (Switzerland) Estradiol: a hormone with diverse and contradictory neuroprotective actions Phyllis M. Wise, Shotaro Suzuki, Candice M. Brown (USA) Neurotoxicity of drugs of abuse—the case of methylenedioxyamphetamines (MDMA, ecstasy), and stimulant amphetamines Euphrosyne Gouzoulis-Mayfrank, Joerg Daumann (Germany)

Pharmacological aspects
The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders—relation to drug treatment Norbert Müller, Aye-Mu Myint, Markus J. Schwarz (Germany) The neurotrophic and neuroprotective effects of psychotropic agents Joshua Hunsberger, Daniel R. Austin, Ioline D. Henter, Guang Chen (USA)

Brief report
Neuroplasticity in addictive disorders Charles P. O’Brien (USA)

ISSUE COORDINATED BY: David R. Rubinow

235

PhD Norbert Müller. MD. DipPsych Author affiliations: Fishberg Department of Neuroscience. Seattle. NIMH. University of Pennsylvania. Philadelphia. Ludwig-Maximilians-Universität München. Pennsylvania. USA Pierre J. Germany Eric J. MD. Nestler. MD Author affiliations: Department of Psychiatry. Site de Cery. and Obstetrics and Gynecology. MD. Maryland. PhD Charles P. MD. Connecticut. Pennsylvania. New York. PhD Author affiliations: Departments of Psychiatry and Neuroscience. USA Author affiliations: Department of Psychiatry and Psychotherapy. Wise. Switzerland Author affiliations: Department of Psychiatry. USA 236 . USA Phyllis M. Germany David A. Treatment Research Center. Yale University School of Medicine. Mood and Anxiety Disorders Program. PhD Author affiliations: Departments of Physiology and Biophysics). Lewis. Département de Psychiatrie. Bethesda. University of Pittsburgh. Washington. Biology. USA Author affiliations: Laboratory of Molecular Pathophysiology and Experimental Therapeutics. Duman. Lausanne. PhD. O’Brien. University of Washington.Contributors Ronald S. New Haven. Mount Sinai School of Medicine. PhD Author affiliations: Centre de Neurosciences Psychiatriques. NIH. USA Author affiliations: Department of Psychiatry and Psychotherapy. New York. University of Cologne. MD. Magistretti. MD Guang Chen. CHUV. PhD Euphrosyne Gouzoulis-Mayfrank.

. excitotoxicity—not only can the neuroprotective functions of astrocytes be overwhelmed. but rather is a dynamic organ. and inflammation. 237 . the authors highlight the lack of parallelism in reported effects and consequent gaps in our knowledge that must critically be addressed. David Lewis (p 269) performs an anatomical and biochemical dissection of the circuitry of a brain region that mediates cognitive processes known to be disturbed in schizophrenia. In the second Translational research article. Drs Gouzoulis-Mayfrank and Daumann (p 305) turn our attention from neuroprotection to neurotoxicity in their description of the effects of drugs of abuse. the brain is not a collection of structurally invariant components. not as trivial academic conceits. These data suggest that targeted neuroprotective mechanisms together with an understanding of genetic determinants of susceptibility will usher in a new realm of effective and individualized prevention and treatment of depression. remember. In the first Translational research article. astrocytes are major homeostatic defenders of neurons. a remarkable process by which environmental events can be transduced into potentially long-lasting changes in chromatin structure (“chromatin remodeling”) with associated changes in gene transcription. An impressively consistent story implicates opposing effects of stress and depression versus antidepressant therapies on growth factors. classical psychiatric disorders. absence of beneficial effects. In general throughout this volume. This issue of Dialogues in Clinical Neuroscience discusses neuroprotection and neurotoxicity. glutamate signaling. Quite to the contrary. so can disturbances in brain plasticity result in behavioral disturbances and. the dorsolateral prefrontal cortex (DLPFC). Our brains are incredibly plastic—able to learn. Ron Duman summarizes a burgeoning literature demonstrating the structural and cellular effects of stressors and depression as well as the mechanisms underlying these effects. apoptosis. with resultant emergent and characteristic symptomatology. but as well the astrocytes can paradoxically advance the deleterious processes and the onset of disorders like Alzheimer’s disease. unlike what many of us were taught.. but as well they represent compelling explanations for both the development of drug addiction and the behavioral response to stress and to antidepressant treatments. Not only do epigenetic changes represent a form of cellular memory. he describes how developmentally determined deficiencies in γ-aminobutyric acid (GABA) signaling and neuronal synchronization in the DLPFC may result in core cognitive and behavioral deficits in schizophrenia. In the following article. oxidative stress. indeed. exquisitely sensitive to and dynamic modulators of neuronal activity. In the State of the art opening article (p 239). Although the basis of heredity is found in the structure of DNA. Renthal and Nestler (p 257) provide a lucid and yet sophisticated discussion of epigenesis. the basis of much of the behavioral variance in psychiatric disorders is found in gene expression. particularly brain-derived neurotrophic factor. In the third article in this section. While evidence of the neurotoxicity of these agents is substantial. Belanger and Magistretti (p 281) authoritatively trounce the antiquated yet previously prevalent view that glia are largely inert neural components. And just as alterations in gene expression and synaptic connectivity and strength are critical to learning and stress adaptation. environmental and genetic risks alter brain development. but as processes that can now be shown to underpin a variety of psychiatric disorders and that may offer future directions for novel therapeutics. namely MDMA (ecstasy) and the stimulant amphetamines. Of particular clinical relevance are the observations of the anti-inflammatory actions of estradiol and the elegant demonstration that the latency following cessation of ovarian function critically determines the cellular and antiinflammatory effects of estrogen replacement—long latency. Brain morphological and neurochemical abnormalities (particularly involving serotonergic and dopaminergic systems) in animals and brain imaging abnormalities in humans consequent to stimulant abuse are comprehensively reviewed and juxtaposed with reports of behavioral abnormalities. In a technically detailed and yet lucid presentation. Under pathogenic conditions—neuroinflammation. These findings help explain ostensible contradictions in the literature and support the optimism that estradiol and related steroids may yet be “rescued” as neuroprotective therapeutic agents. and Brown (p 297) update our understanding of the dramatic yet highly context-dependent neuroprotective and neuroplastic effects of estradiol. Suzuki. and change in the service of adaptation. mere structural nursemaids. both structurally and functionally.In this issue. resulting in enduring molecular and cellular disturbances in neural circuits. neuroplastic and neurotoxic effects cannot be inferred with certainty absent knowledge of timing and context. Drs Wise. As such. For some psychiatric disorders. In the fifth Translational research article.

. In the second Pharmacological aspects article. Charles O’Brien (p 350) eloquently and convincingly demonstrates that the phenomenology surrounding one psychiatric disorder—drug addiction—can best. Norbert Müller and colleagues (p 319) provide an extensive review of inflammatory processes as they apply to schizophrenia and depression. As such. Mechanisms of action of psychopharmacotherapies and pathogenic contributions of neurotransmitter dysregulation are translated into descriptions of the restoration or perturbation of immune balance. Consideration of immunologic contributions to major psychiatric disorders may generate novel therapeutic interventions for these conditions. in the Brief report. if not only. Rubinow. the originally described mechanisms of action increasingly appear to be relatively primitive. As many psychiatric disorders are systemic illnesses. Finally. antipsychotics. thus paving the way for broader potential future therapeutic indications. MD 238 . While most of the medications in our current psychiatric armamentarium antedate the turn of the century..In this issue. In the first Pharmacological aspects article. respectively. and mood stabilizers—with exquisite attention paid to cell signaling pathways and molecules that mediate the trophic and neuroprotective actions of these drugs. Chen and colleagues (p 333) review the cellular effects of psychotropic drug classes—antidepressants. it should surprise no one that they are characterized and contributed to by immune disturbances. Compelling evidence is presented from animal and human studies for the role of these neuroplastic actions in the therapeutic efficacy of psychotropic agents. treatments designed to restore normal synaptic plasticity in the nucleus accumbens might be predicted to lyse drug-seeking behaviors. be understood as representing neuroplastic changes in susceptible individuals in response to drugs that co-opt our reward/learning pathways. David R.

34 Park Street. these findings have contributed to a fundamental shift in our understanding of the cause and treatment of psychiatric illnesses and the role of neurotrophic and neuroprotective mechanisms. Conversely. © 2009. USA (e-mail: ronald. insults.8 Together. antidepressant.dialogues-cns.2. Related aspects of this work are the effects of environment. This review will present evidence demonstrating neuronal damage.11:239-255. role for damage and protection of neurons in the pathophysiology and treatment of psychiatric illness. including major depressive disorder (MDD) is based on molecular. USA Copyright © 2009 LLS SAS. Yale University School of Medicine. 1.1-4 Advances in human brain imaging have also reported decreased volumes of limbic brain regions implicated in depression. CT 06508. gene expression Author affiliations: Department of Psychiatry. and survival of neurons and glia. Lifetime exposure to cellular and environmental stressors and interactions with genetic factors contribute to individual susceptibility or resilience. and morphological studies in experimental animals and in human patients. Connecticut.duman@yale. All rights reserved 239 www. New Haven. chronic administration of therapeutic agents blocks the effects of stress or leads to induction of neurotrophic and neuroprotective pathways. behavioral and therapeutic interventions can reverse these structural alterations by stimulating neuroprotective and neurotrophic pathways and by blocking the damaging. Studies demonstrating the neuroprotective actions of therapeutic agents that counteract the effects of stress and depression will also be discussed. atrophy. are characterized by structural alterations.7 Conversely. signal transduction. This exciting area of research holds promise and potential for further elucidating the pathophysiology of psychiatric illness and for development of novel therapeutic interventions. cellular stressors. Duman. as well as other psychiatric illnesses. New Haven. growth. Yale University School of Medicine.State of the art Neuronal damage and protection in the pathophysiology and treatment of psychiatric illness: stress and depression Ronald S. and inflammatory effects of stress. has contributed to a fundamental change in our understanding of these illnesses. 3rd floor. demonstrating dysregulation of neurotrophic factors and neuroprotective mechanisms in response to stress and in depressed patients. These structural changes are accompanied by dysregulation of neuroprotective and neurotrophic signaling mechanisms that are required for the maturation. and interactions with genetic factors that increase susceptibility and thereby cause damAddress for correspondence: Department of Psychiatry. Preclinical studies demonstrate that chronic stress causes alterations to the number and shape of neurons and glia in brain regions implicated in mood disorders. 2. and that these changes result from atrophy and loss of neurons and glia in specific limbic regions and circuits.org . 2009.6 Preclinical and postmortem studies of signal transduction pathways and target genes have extended this work at the molecular level. and cell loss in response to stress and depression. and the mechanisms underlying these effects. excitotoxic.5. PhD The discovery that stress and depression. neurogenesis. cellular. LLS SAS Dialogues Clin Neurosci.edu) A Keywords: synapse.

19. Schematic demonstrating the effects of stress and neuroprotective mechanisms on the proliferation. Imaging Genetic factors Increased susceptibility • Trophic support • Excitotoxicity • Inflammation/cytokines • Metabolic support • Viral/toxic load Neuronal & glial proliferation. Cellular/neuronal stress and damage Environment • Stress • Trauma • Illness Neuroprotective mechanisms Life history • Reduce stress • Exercise. These regions include the hippocampus. and fear. cellular growth and survival are intimately controlled by neuronal activity (Figure 1). growth. In addition. most notably decreased cognition. nucleus accumbens. and survival of neurons and glia. and inhibitory control of brain regions that underlie fear and emotion. Together.15. The primary function of the PFC is cognition. diet • Medication Genetic factors Increased resilience age and illness (Figure 1). and survival. Interactions with environment. medications. brain imaging and postmortem studies have identified structural alterations in MDD patients that indicate reductions in dendrite arborization and complexity.3-dioxygenase major depressive disorder N-methyl-D-aspartic acid prefrontal cortex tumor necrosis factor studies have consistently reported that the volume of the hippocampus is decreased 10% to 20% in MDD patients. In addition. and life history also influence these cellular processes. cognition. a structure that contains high levels of receptors for glucocorticoids. and interactions with genetic factors that increase resilience are neuroprotective. Brain imaging studies have reported a significant reduction in the volume of the PFC in MDD patients. and survival Emotional and cognitive function and health Figure 1.9. function. such as exercise. working memory. Conversely.13. cingulate cortex. which could underlie the reported hypofunction of this structure.State of the art Selected abbreviations and acronyms ADT AMPA BDNF IDO MDD NMDA PFC TNF antidepressant treatment -amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid brain derived neurotrophic factor indoleamine 2.14 There is also evidence of a negative correlation with the length of illness and reversal with antidepressant treatment (ADT). including post-traumatic stress disorder (PTSD)16. diet. Normal. which then regulate emotional and cognitive health or illness. and reverse or block the damaging effects of stress. these findings provide compelling evidence for disruption of neurotrophic factors and neuroprotective mechanisms in the pathophysiology of depression.20 Cellular alterations Different types of cellular alterations could account for the volume reductions observed in the hippocampus. Structural/cellular alterations in mood disorders Depression. like most other major psychiatric illnesses. life history of behavior or therapies that reduce stress and enhance neuronal survival. anxiety. It is also notable that hippocampal volume reductions have been reported in other stressrelated illnesses. as well as proliferation. growth.9-12. and decreased numbers of neurons and glia in these brain regions. is the hippocampus. is widely accepted to be caused by neurochemical imbalances in regions of the brain that are known to control mood. and amygdala.15 but additional studies are needed to further examine these relationships and to determine whether the reduction is a result or a cause of depressive illness. Structural alterations One of the regions of interest in depression. This is due to the activity-dependent requirement for expression of neurotrophic factors and other survival pathways and mechanisms that control neurotransmission and neuroplasticity. genetic factors. prefrontal cortex (PFC). growth. 240 . healthy activity of the brain circuits that underlie emotion and cognition also influence cell survival and function as the expression and function of neurotrophic and neuroprotective mechanisms requires neuronal activity. as well as other disorders. all of which could contribute to depressive symptoms (Figure 2).18 The PFC is another “stress-responsive” brain region implicated in depression.17 and schizophrenic patients.

34 Moreover.28 have been reported. suggestive of reduced dendritic arborization and complexity. the stress-induced atrophy of hippocampal and PFC neurons is reversible. characterized by a decreased number and length of apical dendrites. even with continued stress exposure.23-25 Reductions of both astrocytes26 and oligodendrocytes27. the rodent equivalent of cortisol. No. and have shown a reduction in the size of neuronal cell bodies. Cell morphology Early studies of cell morphology found that repeated stress causes atrophy of CA3 pyramidal neurons in the hippocampus. these models have been used to demonstrate that antidepressants can reverse or block the effects of stress on cellular morphology. and a reduction in spine number in response to immobilization stress (Figure 2).32. and proliferation of neurons and glia. PFC pyramidal cell apical dendrites Cellular alterations in animal models of depression Animal models of depression have been used to further elucidate the ultastructural and molecular alterations that underlie the morphological changes observed in MDD patients. Influence of stress on the morphology and proliferation of neurons and neurotrophic factor expression.23. the most consistent finding in studies of PFC is a decrease in the number of glia in MDD patients. size. Images courtesy of Drs G. which might contribute to the therapeutic actions of these agents. although more subtle synaptic changes have been reported. There is one report that the size of neurons in the major subfields of the hippocampus is reduced. chronic administration of certain antidepressants blocks or reverses hippocampal atrophy. damage. 3 . Most notably.Duman Dialogues in Clinical Neuroscience . it is reasonable to speculate that neuronal atrophy. 241 .3.30 More recent studies have shown that pyramidal neurons in the PFC undergo a similar retraction/atrophy of apical dendrites. and the number of spines in the prefrontal cortex (PFC). Aghajanian and R-J. In addition. Given the significant role of glia in providing metabolic support for neurons as well as control of neurotransmitter activity (eg.29.33 In contrast to most neurological disorders. removing animals from stress normalizes the dendritic arborization of pyramidal neurons over a period of several weeks. There were no changes in the numbers of neurons or glia reported in this study or in other qualitative studies. Exposure to immobilization stress decreases the number and length of pyramidal cell apical dendrites. Li.30 This reversibility supports PFC pyramidal cell spines Hippocampal granule cell neurogenesis Hippocampal BDNF expression Figure 2.21 suggesting a reduction in neuropil that could contribute to decreased hippocampal volume in MDD patients. and hypofunction of PFC could be related to the loss of glia. in which the structural alterations and loss of neurons is permanent.Neuroprotection and depression . causes a similar atrophy of hippocampal and PFC neurons. as stress is a critical factor in the etiology of depression. Stress also decreases the birth of new neurons and expression of brain derived neurotrophic factor (BDNF) in the adult hippocampus (HP).22 Control Stress Studies of the PFC and cingulate cortex have been more extensive.Vol 11 .31 Chronic exposure to high levels of exogenous corticosterone.24 In addition.29. 2009 including reductions in the number. Most of these models are based on acute or chronic-stress paradigms. synthesis and reuptake).32.

consistent with the time course for the therapeutic response to antidepressants. dent behavior.38.35.48 Ablation of glia in the PFC decreases sucrose consumption. antidepressants increase the proliferation of neurons and glia in the hippocampus and/or PFC. This complex interaction of gene-environment interactions over the lifespan is thought to contribute to the heterogeneity of depression. and block or reverse the effects of stress.49 Decreased PFC dendrite arborization in response to stress is also correlated with a reduction in attention set shifting. survival. The influence of these factors and insults on cell function and survival could occur rapidly after a single major event or could occur gradually over time with the accumulation of one or more insults. a measure of anhedonia. and by administration of exogenous corticosterone. The proliferation of new neurons is decreased by different types of stress. chronic stress decreases the proliferation of new cells in the adult hippocampus and PFC. 54 Recent studies have also reported an interaction between early life stress or trauma and neurotrophic factors (see below). Interactions of stress and genetic factors have also been reported. metabolic/vascular support. also referred to as allostatic load (Figure 1).36 Interestingly. and electroconvulsive seizures (ECS). These include altered neurotrophic/growth factor support. The dentate gyrus of the hippocampus is one of the few regions of the brain that continues to give rise to new neurons in adulthood. however. and antidepressant medications could result from a number of different mechanisms that alter the proliferation. This has been addressed by blockade studies (ie.State of the art the notion that dendritic alterations represent a type of structural plasticity that has functional consequences. which demonstrate that neurogenesis is required for the actions of antidepressants in certain behavioral models.40 In contrast.43. including restraint. and sleep deprivation.47.41. a recent meta-analysis suggests that additional studies of this polymorphism are required. predator odor. viral. growth. Characterization of the molecular mechanisms and genetic factors that underlie the structural alterations and that play a key role in neuroprotection will provide 242 . indicating a requirement for glial function in this model. depression.39 Chronic stress also decreases the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the hippocampus. other psychiatric illnesses.45.50 These studies demonstrate a causal and/or correlative relationship between cell number and complexity with behavior. footshock.37 In the PFC the proliferation of glia is decreased by exposure to repeated stress38 or corticosterone treatment. including serotonin selective transporter inhibitors. inflammation/cytokines. a PFC-depenImportance of life stress/trauma: gene-environment interactions There is also evidence that exposure to traumatic or stressful life events can have a cumulative effect that increases susceptibility or vulnerability to mood disorders51 (see Figure 1).55 The effects of these cellular stressors and insults are also influenced by genetic factors that can either increase susceptibility to cellular damage. Different classes of antidepressant increase cell proliferation in rats.46 although there are exceptions.41. the rate of neurogenesis is influenced by environmental and endocrine factors. maternal separation.42 These effects require chronic administration (weeks). and stress is one of the most consistent and robust negative regulators (Figure 2).42.53 Studies of genes that increase resilience to stress and mood disorders have also been conducted. excitotoxicity. and function of neurons and glia. as well as treatment of these disorders. norepinephrine selective reuptake inhibitors (NSRIs). or conversely decrease susceptibility and increase resilience and neuroprotection. Behavioral consequences of altered cell morphology A major question is whether the cellular alterations lead to changes in behavior. Cell proliferation In addition to dendritic atrophy. psychosocial stress. in rodents as well as nonhuman primates and humans. focused irradiation or genetic manipulation).44 indicating that this is a common target of ADT.37. Mechanisms underlying structural alterations and neuroprotection: gene-environment interactions Cellular and structural alterations in response to stress. most notably for lifetime stress and the serotonin (5-HT) transporter short allele polymorphism52. and toxic insults.

56 Stress.59-61 These findings provide further support for the hypothesis that the morphological and behavioral abnormalities associated with MDD could result. This includes a reduction of neuronal firing. and FGF2 have also been implicated in the effects of stress.1 Decreased expression of BDNF is observed in the major subfields of the hippocampus. Other important mechanisms to be discussed are glutamate excitoxicity. This section will review key evidence demonstrating dysregulation of neurotrophic/growth factors in stress and depression. Role of BDNF in stress.57 and this effect has been reported with many other types of stress. Because these factors play a critical role in the proliferation.Duman Dialogues in Clinical Neuroscience . and the most widely studied member of this family is brain derived neurotrophic factor (BDNF). depression. and ADT BDNF and related family members. but not the number. depression. These findings suggest that mechanisms that control maintenance of neuronal size and function. The following sections will discuss the major molecular and cellular mechanisms underlying the actions of stress.Neuroprotection and depression . such as neurotrophic factors.63 and epigenetic regulation of BDNF expression in response to chronic social defeat stress. resulting in autophosphorylation of the receptor and interactions with docking proteins 243 . and amygdala. from decreased BDNF expression. the phosphatidylinositol-3 kinase (PI3K). and the phospholipase-C-γ (PLCγ) pathways (Figure 3). apoptosis. and behavior is supported by genetic studies of BDNF. but are also expressed in the adult brain and play a critical role in the survival and function of mature neurons. which are induced by stress and activation of the hypothalamo-pituitary-adrenal (HPA) axis. depression.65-67 The met allele has also been asso- Neurotrophic/growth factors The nerve growth factor (NGF) family has been the focus of much of the work on stress and depression. and growth of neurons during development. 3 . including NGF and neurotrophin-3 (NT-3). that lead to activation of one of three major intracellular signaling cascades: the microtubule associated protein kinase (MAPK). and ADT. The latter will include not only chemical antidepressants. 2009 important information for the diagnosis and treatment of depression. in part. differentiation. differentiation. and counteract stress-induced atrophy. could be critical mediators. including exercise. PFC. including the hippocampus.56 BDNF is expressed at relatively high levels in limbic brain structures implicated in mood disorders. IGF-1.62 BDNF expression is also decreased by adrenal-glucocorticoids. that decreases the processing and release of BDNF. indicating that cell death probably does not play a major role in depression. and ADT. There are several possible mechanisms that could underlie the regulation of BDNF by stress.Vol 11 . and regulation of BDNF Smith and colleagues were the first to report that exposure to immobilization stress results in a dramatic reduction in levels of BDNF in the rodent hippocampus. No. several other growth factors. influence the proliferation. and inflammation/immune responses. reporting decreased levels of BDNF in the hippocampus of suicide-MDD subjects. morphology. growth. In addition. postmortem studies demonstrate a decrease in the size. as BDNF expression is dependent on activity and Ca2+-stimulated gene transcription. but also other strategies that have neuroprotective actions.58 Postmortem studies are consistent with the rodent work. Most of this work has focused on a functional polymorphism. including VEGF. and survival. including those layers where dendritic atrophy (CA3 pyramidal cell layer) and decreased neurogenesis (dentate gyrus granule cell layer) are observed in response to stress. of neurons. As discussed above.57 There is also evidence that downregulation of BDNF by acute stress is mediated by interleukin-1β (IL1β).65 The Met allele has been associated with reduced hippocampal size and decreased memory and executive function in humans.64 Genetic studies of BDNF and interactions with stress A relationship between BDNF. but not acute stress.8 These cascades have been linked to the neuroprotective effects of BDNF. Functional BDNF acts as a dimer to stimulate the intracellular tyrosine kinase domain of TrkB.57 Expression of BDNF in the PFC is also decreased by chronic. as well as regulation of cell proliferation. Val66Met. and acts through a transmembrane tyrosine kinase receptor referred to as TrkB. depression. and survival of neurons and glia in the adult brain. their altered expression or function could contribute to the cellular and morphological changes in animal models of depression and in MDD patients.

Bad. NFkB. GSK-3. fibroblast growth factor receptor substrate. brain derived neurotrophic factor. interleukin-1b. and proliferation of neurons and glia in limbic brain regions. GPCR. phosphatidylinositol 3’-kinase. Sos. G protein coupled receptor. protein kinase B. Shc. guanine nucleotide exchange factor. resilience. FRS. IRS. IKK.State of the art Antidepressant/exercise Stress Inflammation Oxidative stress Aging IL-1 5-HT/NE VEGF/IGF1/FGF2 BDNF GPCR AC Gs Y IRS/FRS Ras Sos Raf Shc Grb2 Sos PI-3K IKK Grb2 PI-3K cAMP MEK Akt PKA Akt IκB ERK NFκB IκB Degradation GSK-3 Bad Rsk NFκB Neuroprotection. fibroblast growth factor-2. ribosomal S6 kinase. cAMP-dependent protein kinase. BDNF. antiapoptosis. nuclear factor kappaB. Raf. resilience. antiapoptotic factor 244 . Bcl-2) Nucleus Figure 3. ERK kinase. NE. kappaB inhibitory protein. serine. CREB. FGF2. MEK.5’-monophosphate. stimulatory G protein. serine/threonine kinase. IL-1b. Activation of these pathways leads to neuroprotection. cAMP response element binding protein. survival. small guanosine triphosphatase. Antiapoptosis. AC. 5hydroxytryptamine. insulin receptor substrate . VEGF. PI-3K. Gs. ERK. Akt. Regulation of neurotrophic/growth factors signaling is decreased by stress and increased by antidepressant treatment. cAMP. norepinephrine. Rsk. 5-HT. PKA. adaptor protein. kappaB inhibitory protein kinase. proliferation Apoptosis CREB Gene expression (BDNF.threonine kinase. survival. IkB. Bcl2. extracellular signal regulated kinase. Ras. IGF-1. cyclic adenosine 3’. proapoptotic factor. Grb2. glycogen synthase kinase-3. adenylyl cyclase. vascular endothelial growth factor. insulin-like growth factor-1. Src homology domain adaptor protein.

that ADT decreases BDNF in this reward pathway.1 These findings indicate that increased expression of BDNF is a common target for different therapeutic strategies. Infusions of BDNF increase hippocampal neurogenesis. Other neurotrophic/growth factors There is now strong evidence demonstrating a role for several other growth factors in the actions of stress. multifactorial illnesses such as depression.95 and BDNF is necessary for the survival of new neurons in response to ADT. Evidence for a direct relationship between the Met allele and neuronal structure has also been reported in rodent models.Neuroprotection and depression .73. for reviews see refs 92. and possibly other trophic factors. and behavioral actions of BDNF The neuroprotective effects of BDNF have been well documented. hypoclycemia. TrkB is also required for antidepressant induction of hippocampal neurogenesis.96 The BDNF receptor.78 A gene-environment interaction is also supported by the genetic association studies of the BDNF Met allele discussed above. 3 .1. neurogenic. but also in vivo.68 There are also reports that patients carrying the Met allele.75-77 These findings are consistent with the hypothesis that induction of BDNF contributes to the neurogenic and behavioral actions of antidepressants. as well as the behavioral actions of antidepressants. and stress does not produce further atrophy of apical dendrites in BDNF heterozygous deletion mutants. No. This is based on studies demonstrating that BDNF is increased by stress in the mesolimbic dopamine system and has a depressive effect in the social defeat model.94. indicating that decreased BDNF underlies the effects of stress.71 A complicating factor in understanding the functions of trophic factors is the possibility that there are opposing. but not acute ADT increases the expression of BDNF in the hippocampus and frontal cortex.1. 2009 ciated with smaller volume of cingulate cortex. hippocampal pyramidal cell dendrite complexity is decreased in BDNF Met allele or heterozygous deletion mutants.73 similar to the actions of stress.75-77 blockade or reduction of BDNF expression increases the susceptibility to the effects of stress. Postmortem studies also demonstrate that BDNF levels are increased in the hippocampus of patients receiving antidepressant medication at the time of death. and conversely. Antidepressants increase BDNF In contrast to the effects of stress. including α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor potentiators.93.83 Other agents known to have antidepressant efficacy also increase BDNF expression in the hippocampus.82. and exercise.84-86 Neuroprotective. excitotoxicity. either young or aged.97 BDNF has also been implicated in the behavioral actions of ADT. In mice expressing the Met allele there is a decrease in the number and length of apical dendrites in both the hippocampus72 and PFC.98-100 and mutant mouse studies demonstrate that BDNF is required for the behavioral actions of antidepressants.74 Similar effects have been observed in PFC pyramidal cells. NMDA receptor antagonists. 245 . This includes studies demonstrating that BDNF increases survival and has neuroprotective actions in models of hypoxia. and this effect is greater in patients with bipolar disorder. is circuitdependent and that findings in one region cannot be extrapolated to others. transcranial magnetic stimulation. and inflammation87-91. have an increased incidence of depression when exposed to stress or trauma. primarily in cultured cell systems. ischemia.59 These effects are thought to occur via activation of cAMP and/or Ca2+-dependent BDNF gene transcription that are activated by ADT.70. BDNF has also been shown to influence hippocampal neurogenesis. region-specific effects of BDNF.Vol 11 . Exposure of BDNF heterozygous deletion mutant mice to stress or blockade of BDNF-TrkB signaling produces a depressive-like phenotype in the forced swim test.73 These findings indicate that a full complement of functional BDNF is required for maintenance of normal dendritic arbor in both the hippocampus and PFC.79 These findings demonstrate that the expression and function of BDNF. demonstrating the clinical relevance of ADT induction of BDNF. BDNF infusions are sufficient to produce an antidepressant response in rodent behavioral models of depression. As discussed above.74 Although deletion of BDNF is not sufficient to produce depressive-like behaviors. chronic.Duman Dialogues in Clinical Neuroscience .69-71 These latter studies highlight the importance of gene x environment interactions in complex.80-82 Induction of BDNF is observed with different classes of chemical antidepressants as well as electroconvulsive seizures.80. except in female mice.

and has been implicated in the pathophysiology of a variety of disorders.111.State of the art depression.109 The role of FGF2 in the proliferative actions of ADT. depression. physical.108 and FGF2 infusions are sufficient to produce an antidepressant response in behavioral models. whereas inhibition of Flk-1 blocks the induction of adult neurogenesis and the behavioral effects of ADT. and even the susceptibility resulting from genetic vulnerabilities (see Figure 1). Neuroprotective and neurotrophic effects of exercise Exercise is reported to increase the expression of neurotrophic/growth factors.105 and social defeat stress decreases FGF2 in the hippocampus.102 In addition. an effect that is dependent on increased expression of IGF-1 and VEGF. serum.123 Functional in vivo measures of glutamate content in the brain using proton magnetic resonance spectroscopy (H-MRS) show elevated glutamate levels in the occipital cortex of depressed patients.103 Chronic unpredictable stress decreases the expression of VEGF. circulating IGF-1. and IGF-1.98.104 A recent postmortem study found that the expression of FGF2 and its receptors (FGFR2 and FGFR3) are reduced in the PFC and cingulate cortex of MDD patients.111 Recent studies have also demonstrated that IGF-1 administration. and mood disorders.102 while ADT increases VEGF expression in the granule cell layer of the hippocampus.123. including BDNF.102. The expression of IGF-1 in the hippocampus is increased by chronic administration of two different monoamine oxidase inhibitor antidepessants. and neurogenesis. is actively transported into the brain and is required for the induction of neurogenesis in response to exercise.118 In addition to the regulation of these growth factors. including schizophrenia.112. and has been shown to play a role in hippocampal neuroplasticity. exercise has also been shown to influence other neuroprotective mechanisms.125 246 .114-117 In addition. fibroblast growth factor 2 (FGF2). and Alzheimer’s disease.110 In addition to expression in brain. or even reversing the damage that can be caused by environmental. amyotrophic lateral sclerosis. memory. or agents that increase IGF-1 levels. produce antidepressant-like actions in behavioral models of depression. Flk-1. Excess glutamate in depression and stress Abnormal glutamate levels and function have been implicated in psychiatric illnesses.111. anxiety. and insulin-like growth factor 1 (IGF-1). increase VEGF expression in the hippocampus. including SSRI.121 This section discusses evidence for excess glutamate in stress related mood disorders. although decreases have been reported in other regions. and psychological stressors. and ADT Excess glutamatergic excitotoxicity is one of the major mechanisms underlying neuronal damage and loss in the brain. chronic ADT increases the expression of FGF2 in cerebral cortex and hippocampus of rodents107.122-124 Glutamatergic abnormalities have been reported in the plasma. as well as its receptor. on both neurons and glia. and brain tissue of individuals suffering from mood disorders. FGF2.114 IGF-1 has also been shown to underlie the neuroprotective effects of exercise against different types of brain insults.113 Together. epilepsy. and pharmacological strategies for intervention and treatment. The opposing actions of stress and ADT on VEGF suggest a possible relationship between neurogenesis and behavior.120. cerebrospinal fluid (CSF). stroke induced ischemia or trauma) and neurodegenerative disorders (eg.119 These positive.101 but is also expressed in the brain in both neurons and glia. VEGF is sufficient to induce neurogenesis and produce antidepressant effects in behavioral models of depression.106 Conversely. indicating that VEGF is a common downstream target of these treatments. NSRI.104 Different classes of chemical antidepressants. is currently being investigated. exercise increases neurogenesis in the adult hippocampus. including vascular endothelial growth factor (VEGF). derived primarily from the liver. and ADT. Huntington’s chorea. including those resulting from acute insult (eg. Stress has a greater effect on newborn cells associated with endothelial cells than nonvascular associated cells. VEGF. and ECS. these findings suggest that peripheral production and/or the central actions of IGF-1 could be novel targets for the treatment of depression. Glutamatergic excitotoxicity: stress. VEGF was originally characterized as a vascular permeability factor and an endothelial cell mitogen. neuroprotective actions make exercise one of the key behavioral factors for protecting. the cellular mechanisms that contribute to glutamate excitotoxicity.

kainiate. including extracellular signal-related kinase (ERK).120.121. prolonged hypoxia.138 These effects are mediated in part by increased expression of glial excitatory amino acid transporters. These topics have been extensively covered by a number of recent reviews. are reported to have antidepressant efficacy in rodent models and in clinical trials. have antidepressant effects in rodent behavioral models and in depressed patients. most studies do not report a loss of neurons in post- mortem tissue from depressed patients. and cAMP response element binding (CREB) can serve as neuroprotective targets for excitoxicity. Glutamate and neuroprotection: therapeutic targets Glutamate neurotransmission is controlled by a complex system of pre. However. These include oxidative stress resulting in generation of reactive oxygen species (ROS) and nitric oxide. including excitotoxins and ischemia. such as those that would occur during stroke-induced ischemia.121. Clinical and preclinical studies are currently underway to further test the therapeutic efficacy and mechanisms underlying the actions of riluzole. as well as for buffering intracellular Ca2+ that protects against cell damage.123 Uncontrolled elevation of intracellular Ca2+ leads to further loss of Ca2+ buffering and homeostasis.129.120. and neurodegenerative illnesses. However. and expression of glutamate receptors.123.32.123 Blockade of the NMDA ionotropic receptor represents another primary target for neuroprotection.29. including the ability to decrease glutamate and increase neurotrophic factor expression.Duman Dialogues in Clinical Neuroscience . Microdialysis studies have shown that stress increases extracellular levels of glutamate in the PFC and hippocampus. although with limited efficacy.Vol 11 . These mechanisms are typically overcome only by severe conditions. notably riluzole and ceftriaxone.132. Lamotragine is another compound that acts in part by decreasing glutamate release and is used for treating mood disorders. providing further evidence that the actions of ADT involves this neurotransmitter system.137 The actions of memantine 247 .130 Stress or glucocorticoid treatment also increases the susceptibility to other types of neuronal insults.127 consistent with the possibility that atrophy of CA3 neurons arises in part through increased glutamate neurotransmission. neurological. trafficking. regulation of tropic factor signaling cascades. as well as decreased neuronal cell body size in postmortem brains of depressed patients.137 A brief discussion of the major glutamatergic targets will be discussed here. Agents that increase this process. such as riluzole and ceftriaxone. including ionotropic and metabotropic subtypes. which results in necrotic cell death characterized by swelling. and eventually inflammation and cell lysis. excess glutamate is still thought to play a role in psychiatric illnesses.123. membrane damage. although this is a complex issue as glutamate is the major excitatory neurotransmitter in the brain.123 Reductions in the number or function of glia are thought to play a role in the atrophy of limbic brain regions observed in brain imaging studies.136. In addition.128. including AMPA. and then to a cascade of events that contribute to cell damage and death.131 There are several possible mechanisms that could contribute to the overactivation of glutamate in response to stress and in depression. including a decrease or loss of mechanisms for inactivation of glutamate.132. agents that block the NMDA channel.and postsynaptic sites. Akt. No.135 There are multiple sites for controlling glutamate release and activity at pre. or in animal models. which is the primary mechanism for inactivation of glutamate neurotransmission.121. DNA degradation. 2009 Preclinical studies also demonstrate a role for glutamate in the actions of stress. One of the key targets for regulation of glutamate is glial reuptake.126. and this has resulted in targeting glutamatergic sites for development of therapeutic agents for mood disorders.Neuroprotection and depression .and postsynaptic receptors. as well as for other psychiatric. uncontrolled seizures or head trauma.129 This hypothesis is supported by studies demonstrating that N-methyl-D-aspartic acid (NMDA) receptor antagonists attenuate stress-induced atrophy of CA3-pyramidal neurons. and NMDA type receptors. and potentially useful therapeutic compound. Glial cells are responsible for the reuptake and inactivation of glutamate from synaptic and extrasynaptic sites. making this an interesting.132-134 Mechanisms of glutamate excitotoxicity Glutamate neurotoxicity results from excessive flux of Ca2+ via ionoptopic receptors. 3 .123.123. most notably memantine and ketamine. As discussed above. Riluzole also has several other interesting properties.133 Recent studies demonstrate that agents that increase glial reuptake of glutamate. There is also evidence that chronic ADT regulates the phosphorylation. are reported to have antidepressant actions in clinical trials and rodents.

Bax and Bak insert into the mitochrondrial membrane and promote the release of cytochrome C. Drugs acting at these receptors are reported to have anxiolytic effects in rodent models.142. The idea of using drugs that enhance AMPA receptor function would appear to be counterintuitive given the possibility of an overactive glutamate system. which includes the Bcl-2 family of proteins. Both agonists and antagonists of group II receptors have shown promise.135 There is a postmortem report of low levels of apoptosis in the temporal cortex and hippocampus of depressed patients. leading to activation of capases 9 and 3. but slow the inactivation or desensitation of the receptors. which is activated by excess glutamate. located at presynaptic sites and on glia and regulate glutamate release. which in turn binds to the apoptotic activator factor (Apaf1). These agents do not directly stimulate AMPA receptors. and ADT Analsysis of postmortem tissue and rodent models has provided some evidence for apoptotic cell death and/or signaling in depression and stress.139. This possibility is supported by a recent study demonstrating that a selective NR2B receptor inhibitor. results in an antidepressant response within 6 to 12 hours.151 248 . which leads to disinhibition or activation of glutamatergic transmission.149 and chronic unpredictable stress increases the number of caspase 3 positive neurons in the cerebral cortex. but apoptotic signaling pathways are also regulated in the adult brain and influence the number and function of mature cells. Upon activation of apoptotic pathways. which results in energy-dependent death. demonstrate positive antidepressant-like effects in rodent models of depression. cytochrome C. Regulation of apoptosis by depression.136 Group I receptors. with several studies demonstrating a rapid and sustained antidepressant response in approximately 60% of patients tested. Further studies are needed to identify safer drugs that have rapid antidepressant effects similar to ketamine.143 and by a recent report that the behavioral actions of ketamine are blocked by inhibition of AMPA receptor activity.606. The latter possibility is supported by studies in rodents demonstrating that NMDA channel blockers increase BDNF expression in limbic structures. Bcl-2 and Bcl-xl) that antagonize proapoptotic factors (eg. with greater effects when coadministered with other antidepressants. In particular. which require weeks or months of treatment before a therapeutic response is observed.147 The Bcl-2 family includes antiapoptotic factors (ie. the hypothesis that blockade of the extrasynaptic NR2B receptor subtype. stress.150 Maternal separation of rats is also reported to increase cell death in the dentate gyrus of hippocampus. produces a rapid antidepressant response in treatment resistant MDD patients. However.141 Another possible mechanism to account for the rapid actions of these agents is via blockade of NMDA receptors on GABAergic inhibitory neurons. indicating stimulation of neuronal activity. have also been targets of interest.123.144 The metabotropic glutamate receptors represent another interesting and diverse set of targets for drug development. and this effect is sustained for at least 7 days. The most direct mechanism to explain the antidepressant action of ketamine is its direct inhibitory effect on NMDA receptors. and caspase activation.146 Programmed cell death (apoptosis) in stress and depression Programmed cell death is a critical mechanism for regulation of the appropriate complement of neurons during development. with reports that mGluR2/R3 antagonists have antidepressant actions and agonists showing anxiolytic and antipsychotic effects. particularly mGluR1/R5 subtypes located at postsynaptic sites as well as on glia.145 Allosteric AMPA receptor potentiator (ARP) agents make up another interesting group of drugs.123.135. These effects are dramatic compared with all other chemical antidepressants.State of the art have been more modest. underlies the therapeutic action of ketamine has received the most attention. CP-101. However. Apoptosis is a highly regulated signaling process. 148 Rodent studies demonstrate that social stress increases the number of apoptotic cells in the hippocampus and temporal cortex. Most promising is a clinical report demonstrating antipsychotic efficacy of an mGluR2/3 agonist. which were first developed for enhancing cognition. influence both the function and release of glutamate. mGluR2 and R3. which produces transient and mild psychotomimetic effects. preclinical studies of these agents. reports on ketamine have been extraordinary. Bax and Bak). a cytosolic adaptor protein.140 A single intravenous dose of ketamine. which have all been resistant to other chemical antidepressants. Group II receptors.

and recent studies demonstrate a role for other aspects of mitochondria function in the pathophysiology and treatment of mood disorders.170). and tumor necrosis factor (TNF)α. There are also several studies that have examined levels of apoptotic signaling proteins in models of stress and ADT. including neurotransmission.162 Mitochondria play a primary role in the storage. alterations of neurotransmitter systems. including IL-1. trauma.154. decreased neurotrophic factor expression. processing. including ERK and Akt. and thereby stimulate inflammatory processes.154 Conversely.Neuroprotection and depression .153. Also of interest are studies of interferon-α. these effects can result in significant actions on neuronal and glial function and cell survival or death. IL-1β. but that also can have damaging effects on cells and tissue. and release of proteins involved in apoptosis. including activation of the HPA axis. and induction of antiapoptotic factors such as Bcl-2. Chronic unpredictable stress is reported to decrease levels of the antiapoptotic factors Bcl-2 and Bcl-xl.164-167 Inflammatory and immune processes can lead to multiple actions that have acute protective actions.Vol 11 . An inverse correlation between levels of TNFα and treatment response has been reported.163 tem. which increase cell survival in part via inhibition of apoptotic. used for the treatment of hepatitis or cancer. it is also now clear that psychological stress. TNFα and depression One of the most consistently altered proinflammatory cytokines in depressed subjects is TNFα.156 Chronic administration of lithium or valproate also increases Bcl-2 in the hippocampus and PFC. Polymorphisms of the adaptor protein Apaf1 were found to be associated with major depression.168.169 TNFα immunotherapy also causes depression. can activate the innate immune sys- 249 . the preclinical and clinical studies provide strong support for TNFα receptors. particularly TNFR2. This includes many of the same actions implicated in the responses to stress and depression.158-160 Antidepressants also influence other signaling cascades that indirectly influence apoptotic processes. that have been implicated in the pathophysiology and treatment of depression. stress.173 Taken together. chronic ADT increases the expression of Bcl-2 and/or Bcl-xl in limbic brain regions. but does not influence levels of Bax. 3 . There are several proinflammatory cytokines of interest. it is also notable that certain members of the Bcl-2 family have also been implicated in other cellular functions.172 and that TNFα receptor null mutant mice have an antidepressant phenotype in the forced swim and sucrose consumption tests. and abnormal or autoimmune responses. IL-6. No. including depression and other psychiatric disorders.Duman Dialogues in Clinical Neuroscience .161 Finally. However.153 Administration of a high dose of adrenal-glucocorticoids reduces Bcl-2 levels. for a more thorough review see ref 167.152 These polymorphisms increase the activity of caspase 9 and would thereby increase the vulnerability of neurons to apoptotic cell death. including infection.155.157 The antiapoptotic actions of lithium and valproate have also been demonstrated in studies of cultured cells. and this effect corresponds with increased sensitivity to excitotoxic damage. elevating cytokine production.135.167 Depending on the severity and length of the inflammatory response. which results in depressive-like symptoms in a large number of patients.171 This finding is supported by preclinical studies demonstrating that TNFα infusions produce a prodepressive effect. as targets for the treatment of mood disorders. Moreover. and depression There is also strong evidence that the proinflammatory cytokine IL-1β plays a key role in the pathophysiology of Inflammation/immune responses Inflammation and immune responses are major factors contributing to the etiology and pathophysiology of many medical illnesses. a recent large clinical trial using an antibody neutralization approach demonstrated significant antidepressant effects of TNFα reduction. stroke. which could be involved in the actions of stress and ADT. indicating that this cytokine may contribute to the etiology of mood disorders and is not simply a marker for depression (for reviews see refs 168. such as social stress. 2009 Genetic association studies have also provided evidence for a link between apoptosis signaling and depression. and increased oxidative stress. Most notable are the effects of stress and ADT on neurotrophic factors and related signaling cascades. Here we discuss a few of the most interesting targets for treatment of depression. Inflammation can be caused by other medical conditions.

These studies indicate that an IDO inhibitor. 3-hydroxyanthranilic acid oxygenase (3-HAO) that is involved in the synthesis of quinolinic acid. ii) reports that IL-1β produces stress like effects.185. this work will define and describe the mechanisms underlying individual variations of illness. indoleamine 2. can also be used once a person has become ill. ❏ Acknowledgements: This work is supported by USPHS grants MH45481 and 2 P01 MH25642 and by the Connecticut Mental Health Center.184 Studies are currently underway to determine if blockade of peripheral. combined with genetic information will ultimately provide tailored approaches for highly specific and efficacious treatments for depression and other illnesses. including activation of the HPA axis.3-dioxygenase (IDO). and a more complete characterization of these complex alterations and signaling mechanisms will require extensive resources and time. and in mice that are deficient in IDO. identification of genetic polymorphisms that impact these pathways and systems and that influence susceptibility or resilience to illness is a major area of research that will continue to develop and unfold. 1-methyltryptophan. and that the IL-1β signaling is a relevant target for drug development.185 Increased IDO has also been positively correlated with depression. and Drs G. and behavioral responses in rodent models181. Changes in lifestyle and behavior can reduce stress and exposure to environmental factors that influence cellular risk and damage and prevent illness. We would also like to thank Mr Xiaowe Su for assistance with literature research. The induction of IDO then results in diversion of tryptophan from the synthesis of serotonin to kyneurenic acid. Together. this work is still at a relatively early stage. most notably quinolinic acid. and possibly an inhibitor of 3-HAO.182 and produces anhedonia and disrupts incentive motivation in rodent models183. the results of this work can be used to formulate a comprehensive approach for the prevention and treatment of psychiatric illnesses. Aghajanian and R-J.185 In addition. However. could have efficacy for the treatment of depression and related mood disorders.174. and thereby provide protection. These approaches. 250 . This work was conducted using a bacterial immune activation model. which induces a long-lasting induction of interferon and results in depressive behaviors in animal models. and in elucidating the molecular signaling pathways and mechanisms that underlie these changes.186 The results demonstrate that BCM-mediated immobility in the forced swim test is reversed by an IDO inhibitor. Development of therapeutic agents that target neuroprotective mechanisms. Interferon and IDO Recent studies demonstrate that one of the key factors contributing to the depressive actions of inflammation and activation of the innate immune system is the induction of a tryptophan degradative enzyme. although a direct causal relationship has not been demonstrated. regulation of monoamines. which can be further converted to toxic metabolites. which is then responsible for the increased levels of IDO. Chronic inflammation and infection can lead to sustained induction of interferon. as well as behavioral interventions that enhance the activity and function of specific neural circuits. at the cellular and anatomical levels in stress-related mood disorders and other psychiatric illnesses. Bacille Calmette-Guerin (BCM). Summary and future directions Significant advances have been made in characterizing the neuronal and glial damage. BCM also increases the expression of a downstream enzyme. as well as central IL-1β signaling is sufficient to block the effects of stress and produce antidepressant actions. or structural alterations. A recent study has now provided direct evidence that induction of IDO underlies the depressive behaviors caused by inflammation/activated immunologic conditions. Moreover. v) our report that CUS-induced anhedonia and decreased neurogenesis produced by is blocked by pharmacological inhibition or null mutation of IL-1β receptors.State of the art stress and depression. iv) preclinical reports that IL-1β decreases hippocampal neurogenesis and underlies the decrease observed in response to stress184.175 These findings include: i) clinical studies reporting an increase in serum levels IL-1β in MDD176-180. When combined with studies of environmental risk factors and lifetime history of stress. Evidence for IDO in depression is supported by studies demonstrating that decreased levels of tryptophan and increased kyneurenin is associated with inflammation and depression. Li for providing images of PFC dendrites in Figure 2. iii) evidence that IL-1β contributes to conditioned fear and depressive like behavior.

La exposición a lo largo de la vida a estresores celulares y ambientales. 2002. 11.6:151-160. Sporn J. Hippocampal atrophy in recurrent major depression. Sheline Y. Magnetic resonoance imaging study of hippocampal volume in chronic. L’exposition durant la vie aux agents stressants cellulaires et environnementaux et les interactions avec des facteurs génétiques participent à la susceptibilité individuelle ou à la résilience.23:921-939. Nestler EJ. Ces modifications structurales s’accompagnent d’une dysrégulation des mécanismes de signalisation neurotrophiques et neuroprotecteurs nécessaires à la maturation. 18. No. los cuales son requeridos para la maduración. al igual que otras enfermedades psiquiátricas. Gurvits T. Sheline Y.11:520-528. 1995. Biol Psychiatry. 2004. 9. Bremner JD. 4. Kononen M. À l’opposé. 3. An update on regional brain volume differences associated with mood disorders. Am J Psychiatry. Heckers S. Lésions et protection neuronales dans la physiopathologie et le traitement des maladies psychiatriques : stress et dépression Notre compréhension du stress et de la dépression. 12.48:813-829. Sheline Y. Hippocampus. la croissance et la survie des neurones et de la glie. Estos cambios estructurales se acompañan de una falta de regulación de los mecanismos de señales neuroprotectoras y neurotróficas. Esta interesante área de investigación abriga potenciales esperanzas para favorecer la dilucidación de la fisiopatología de las enfermedades psiquiátricas y el desarrollo de nuevas intervenciones terapéuticas. The molecular neurobiology of depression. 8.152:973-981. Drevets W. 10. Am J Psychiatry. Psychol Med. 2009 Daño y protección neuronal en la fisiopatología y el tratamiento de la enfermedad psiquiátrica: el estrés y la depresión El haber descubierto que el estrés y la depresión. Biol Psychiatry. comme d’autres maladies psychiatriques. Nat Neurosci. Newton SS. Tanis K. 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182. et al. Hayley S. In search of the Holy Grail for the treatment of neurodegenerative disorders: has a simple cation been overlooked? Biol Psych. Increased plasma concentrations of interleukin-6.5:357-373. Vandoolaeghe E.Connor T.Merali Z. fatique. Etanercept and clinical outcomes. 2002. Laciak M. No. Intracerebroventrivular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock.59:775-785. J Neurosci.Jonas E. Kenis G. Ann N Y Acad Sci.Chuang D. Caliyurt O. Sobieska M.Maier S. 1998. 2009. Hoit D. Pharmacol Rep.Coyle J. Wiktorowicz K. 2008. stress and depressive illness.22:370-379.62:583606. Cytokine production and treatment response in major depressive disorder. Meltzer HY. Cytokines. Leonard BE. An antidepressant mechanism of desipramine is to decrease tumor necrosis factor-alpha production culminating in increases in noradrenergic neurotransmission. 3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. 3 . Stress. 160. Duman. Vardar E.274:6039-6042. Manji HK.29:4200-4209. 178. 2009. Cytokines as a stressor: implications for depressive illness. 2009. 2003. Abay E.105:751-756. Anisman H.105:751-756. 167.Anisman H.695:279-282. Neuropsychopharm. 180. Stress. Lancet.170:429-433. Vedder H. machado-Vieira R.Vol 11 .16:513-524. Induction of IDO by bacille Calmette-Guerin is responsible for development of murine depressive-like behavior. 161. A prominent role in neuroprotection against excitotoxicity. 1995. Turrin N. 163. IL-1B is an essential mediator of the anti-neurogenic and anhedonic effects of sress. Andre C. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. 173. Int J Neuropharmacol.Simen B. 172. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder.Mikova O. Neurosci Lett.Neuroprotection and depression .34:4-20. Eur Neuropsychopharm. Mackiewicz A. Duman RS. Ignatowski TA. Wang Y. Finding the intracellular signaling pathways affected by mood disorder treatments. Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. IL-1 receptor null mice show decreased anxiety and enhanced fear memory. Brain Behav Immun. Rebey M.Lanquillon S. 2008. 169. Annals NY Acad Sci. Maletic V. 164. Duman CH. Watkins LR. 162.Koo J. et al. Merali Z. Raison CL. 168. 2009.Sluzewska A. 165. In press. Yuan P.Grippo A. 2009. 1995. Neurosci. et al. Neuropsychobiology.Levine J. Yakimova R. 177.60:771-782. Depression. Neuron. Brain Res. 2006. 2008. Chuang DM. soluble interleukin-2 and transferrin receptor in major depression. Psychopharm. Rybakowski JK. Krieg JC. 2005. 2006. 2009. Bosmans E. Barak Y. 2002. Reynolds J. Brau P. soluble interleukin-6.O'Connor J. 170. Tyring S.62:4-6. Hickman JA. Int J Neuropsychopharmacol. 176. Du J.65:732-741.182:3202-3212. Simen AA. 166.34:301-309. J Immunol.133:519-531.O'Connor J.11:203-208.Chen R. 255 . Antiapoptotic action of lithium and valproate. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for "free chow" and "earned" sucrose intake. Modulation of synaptic transmission by the BCL-2 family protein BCL-xL.367:29-35.12:805-822. 1999. Biol Psychiatry. Duman RS. 184.165:413-418. Duman RS. 185.Koo J. Psychopharmacology (Berl). J Neurosci.38:157-160. Brennan K.Anisman H. Biol Psych. Bening-Abu-Shach U. Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Merali Z.Koo J. Andre C. 2009. stress and immunological activation: the role of cytokines in depressive disorders. Lawson MA. 2007. Int J Neuropsychopharmacol.Duman Dialogues in Clinical Neuroscience . J Biol Chem.Maes M.Bielecka A. 2003. 2000. RS. Life Sci. 2003. Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Ranjan R.Chuang D. Proc Natl Acad Sci U S A.1053:195204. Bosmans E. J Affect Dis.Bachman R. 175. 179. depression and cardiovascular dysregulation: a review of neurobiological mechanisms and the integration of research from preclinical disease models. Papp K.Tuglu C.762:474476. et al. 2009 157. Rapoport A. 2001.Anisman H. Manji HK. 174. Chengappa KN. Johnson AK. J Psych Neurosci. Maes M. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. 159. Spengler RN. TNF alpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting. and depression in psoriasis: double-blind placebo-controlled randomized phase III trial. Obuchowicz E. 158. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. et al. The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Duman RS.Khairova R. 1999. Cerebrospinal cytokine levels in patients with acute depression.23:8423-8431.12:561-578. Lawson MA. 1995. 2005. Barak V. Bergmans R. 171. Kara SH.Miller A. 181. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. 2003.40:171-176. 183. 2009. Sud R. Gottlieb A.12:1-12. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2. 186. IL-1B is an essential mediator of the anti-neurogenic and anhedonic effects of sress. Soc Neurosci Abst.

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yet their genetic basis remains poorly understood despite substantial advances in whole genome sequencing techniques. Increasing evidence indicates that changes in gene expression in neurons. glucocorticoid receptor. many of these chromatin remodeling mechanisms are highly stable. BDNF.11:257-268. The interactions between the environment and the genes that give rise to specific phenotypes are termed “epigenetic. PhD Alterations in gene expression are implicated in the pathogenesis of several neuropsychiatric disorders. 2009.2 Importantly. including drug addiction and depression. The strong control exerted by chromatin remodeling on gene expression. contributing to the maintenance of specific gene expression programs in the correct tissues throughout the life of an individual. neurons vs hepatocytes). USA (e-mail: eric. Nestler) Address for correspondence: Eric J.dialogues-cns. which has remained more difficult to explain mechanistically. the field is also investigating the environmental component of family history. DNA methylation. New York. Eric J. NY 10029.nestler@mssm. histone acetylation. are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. and bioinformatic approaches that are being used to understand the complex epigenetic regulation of gene expression in brain by drugs of abuse and by stress.”1 An example of this process is observed in cellular differentiation. Support for this hypothesis has been observed in animal models of psychiatric illness. Mount Sinai School of Medicine. Mechanistic insight into this process has recently been uncovered. Mount Sinai School of Medicine.Tr a n s l a t i o n a l r e s e a r c h Chromatin regulation in drug addiction and depression William Renthal. Keywords: chromatin remodeling. in the context of animal models of addiction and depression. This is due in part to the vastly different sets of genes expressed between distinct cell types (eg. despite their identical DNA templates. histone methylation. New York. Dallas. These advances promise to open up new avenues for improved treatments of these disorders. Fishberg Department of Neuroscience. The University of Texas Southwestern Medical Center. stress Author affiliations: Medical Scientist Training Program. One hypothesis is that environmental stimuli alter gene expression patterns in certain brain regions that ultimately change neural function and behavior. molecular. where unique chemical signals induce totipotent stem cells to differentiate into genetically identical cell types with vastly different functions. as well as in human patients. cocaine. Nestler. USA (William Renthal).edu) Copyright © 2009 LLS SAS.org F 257 . Nestler. MD. All rights reserved amily history is one of the greatest risk factors for psychiatric disorders. and the potential stability of chromatin www. thereby providing unique gene expression profiles in response to specific environmental cues. © 2009. New York. Texas. PhD. While the search for genetic mutations continues at a rapid pace. and involves the transduction of unique environmental signals into precise and highly stable alterations in chromatin structure that ultimately gate access of transcriptional machinery to specific gene programs. USA (Eric J. Fishberg Department of Neuroscience. This review discusses recent findings from behavioral. LLS SAS Dialogues Clin Neurosci.

endocrine abnormalities Imprinting+mutation Cortical atrophy. abnormal cardiac conduction. mating switching and sucrose non-fermenting complex.Tr a n s l a t i o n a l r e s e a r c h Selected abbreviations and acronyms BDNF cAMP CREB H HAT HDAC HDM HMT brain derived neurotrophic factor cyclic adenosine monophosphate cAMP-response element binding protein histone histone acetyltransferase histone deacetylase histone demethylases histone methyltransferase mechanisms. hypotonia X-linked inheritance Psychomotor retardation Craniofacial and skeletal abnormalities X-linked. ribosomal S6 kinase 2. and 16 Abnormal CTG repeat expansion at the 3’UTR of the DM1-Protein Kinase gene favors chromatin condensation. Dnmt3B. DNA methyltransferase 3B. UTR. methyl-CpG-binding protein 2. It is also interesting to note that certain neurological and psychiatric diseases are caused by rare genetic mutations in chromatin remodeling enzymes (Table I). fragile X mental retardation protein 1. facial. cyclic AMP-response element binding protein. insulin-dependent diabetes. CREB. long and narrow face with large ears. splenomegaly. and genital anomalies Autosomal recessive Mild mental retardation Marked immunodeficiency. cerebellar dysmyelination. epigenetic research in psychiatry is aimed Clinical features Autosomal dominant inheritance Mental retardation Abnormal facial features. cognitive abnormalities Disease Rubinstein-Taybi syndrome Chromatin defect Heterozygous mutations in CBP Fragile X syndrome Hypermethylation of DNA at the FMR1 and FMR2 (Fragile X mental retardation-1. they directly illustrate how disruption of chromatin regulation can profoundly affect neural function and lead to complex behavioral abnormalities. X-linked (ATR-X) Immunodeficiency–centromeric instability–facial anomalies syndrome (ICF) Myotonic dystrophy Prader-Willi syndrome Angelman syndrome Mutations in ATRX gene. untranslated region. which can interact with CREB and CBP and can phosphorylate H3 in vitro Mutations in MeCP2 Alpha-thalassemia/mental retardation syndrome. testicular atrophy. Thus. make chromatin regulation a prime candidate for mediating aspects of the long-lasting neural plasticity that ultimately results in psychiatric syndromes. DMPK. CBP.2) promoters. affecting expression of many neighboring genes Imprinting (DNA methylation) of maternal chromosomal region 15q11-13 Imprinting (DNA methylation) of paternal chromosomal region 15q11-13 Table I. XH2. FMR1. premature balding Imprinting+mutation Mild mental retardation. While these mutations are rare. CREB binding protein. affecting predominantly girls Pervasive developmental disorder associated with arrested brain development. 9. RSK2. encoding the X-linked helicase-2 (XH2) – a member of SWI/SNF family of proteins Defective chromatin remodeling thought to downregulate the α-globin locus Mutations in Dnmt3B Hypomethylation at centromeric regions of chromosomes 1. myotonia. facial anomalies Autosomal dominant Mild mental retardation. macro-orchidism. blunted growth X-linked inheritance Most common inherited form of mental retardation. Xlinked helicase 2 258 . skeletal. caused by trinucleotide repeat expansion Coffin-Lowry syndrome Rett syndrome Mutation in RSK2 (ribosomal S6 kinase-2). SWI/SNF. DM1 protein kinase. Examples of diseases of chromatin remodeling. MeCP2. and autistic-like behavior X-linked inheritance Mental retardation Hemolytic anemia. cognitive decline. signs of autistic behavior Macrocephaly.

No. but histone acetylation can occur on other histone proteins as well as in their globular domains. depression. as is seen with genetic imprinting or X-inactivation.6 Genome-wide studies indicate that high levels of histone acetylation in gene promoter regions are generally associated with higher gene activity. 9 Most genome-wide studies of histone acetylation have focused on acetylation of the N-terminal lysine residues in histones H3 and H4. where DNA methylation contributes to lifelong gene silencing. it was thought that this elaborate chromatin structure only functioned to condense meters of DNA into the microscopic cell nucleus. great progress is being made in identifying epigenetic alterations in many neuropsychiatric syndromes. 9. Initially.13. Histone acetylation is a dynamic process. while low levels of acetylation correlating with reduced gene activity. phosphorylation. 10) are only expressed in specific tissues such as heart and brain and are much larger enzymes that also contain an N-terminal regulatory domain that enables them to be shuttled in and out of the nucleus in a neural activitydependent manner. but it is now known to participate directly in gene regulation. Class I HDACs (eg.11 Histone deacetylases (HDACs). H2B. 7.5 cellular mechanisms exist to modify and remodel chromatin structure to allow for the coordinated expression of specific transcriptional programs and the silencing of others. the apparent stability of some epigenetic mechanisms in vivo. H3. 2.3 which then supercoil to form a highly condensed structure (Figure 1). they are much less efficient enzymes than Class I HDACs. despite 259 .Vol 11 . Many HATs can also acetylate nonhistone proteins such as transcription factors (eg. this review briefly discusses the molecular machinery underlying epigenetic mechanisms in brain. and some transcription factors (eg. Focusing on drug addiction and depression. methylation of DNA. and Rett syndrome.4. ATF2 [activating transcription factor 2]. DNA wraps around histone octamers made up of two copies of histone H2A.6 The in vivo mechanisms which maintain easily reversible histone modifications (eg. Ultimately. methylation. HDAC11. controlled by specific enzymes which either add or remove the acetyl mark. An especially important aspect of certain chromatin modifications is their apparent stability.7 As mentioned earlier. and H4. 5. While this field is still in its infancy.14 There is currently one Class IV HDAC. and associated nonhistone proteins in the cell nucleus. histones.Renthal and Nestler Dialogues in Clinical Neuroscience . Histone acetylation Acetylation of histone lysine residues reduces the electrostatic interaction between histone proteins and DNA. DNA methylation) on other genes are currently not clear. much in the same way as environmental cues differentiate a stem cell into specific lineages. all types of chromatin modifications identified to date are potentially reversible and have specific enzymes or processes which mediate the addition or removal of each mark. including drug addiction.Chromatin regulation in drug addiction and depression . or several other covalent modifications of histones. 3 .10. and may also deacetylate other cellular substrates. 3. and it has characteristics of both Epigenetic mechanisms Chromatin is the complex of DNA. Because DNA is tightly associated with histones and often embedded deep within chromatin supercoils. p53). Class II HDACs (eg. which relaxes chromatin structure and improves access of transcriptional regulators to DNA (Figure 1). dozens of potential modifications that occur at many distinct histone residues summate to determine the final transcriptional output of a given gene.12 While Class II HDACs can deacetylate histones. HDAC4. are divided into four classes. acetylation) on some genes or delete highly stable marks (eg. and many others. HDAC1. and 8) are ubiquitously expressed and likely mediate the majority of deacetylase activity within cells. Alzheimer’s disease. genetic mutations in many of these chromatin remodeling enzymes are associated with severe neurological and psychiatric disorders (see Table I). There are over a dozen known histone acetyltransferases (HATs) which catalyze the addition of acetyl groups onto lysine residues of histones with varying degrees of specificity. 2009 at identifying whether environmental stimuli induce changes in chromatin structure which ultimately contribute to transcriptional programs in neurons that cause psychiatric illness. and how their dysregulation may contribute to these chronic psychiatric illnesses. schizophrenia. with each modification either directly altering histone-DNA interactions or serving as a mark that recruits specific proteins to positively or negatively regulate the underlying gene’s activity.8 However.6 Such modifications typically occur on N-terminal histone tails and include acetylation. CLOCK) even possess intrinsic HAT activity that contributes to gene activation. among others. which remove acetyl groups from histones.

Tr a n s l a t i o n a l r e s e a r c h A Histone tail DNA H2B H4 H3 H2A Histone A M P Acetylation Methylation Phosphorylation Permissive B Active Histones A Histone Transcription factor tail + A A P M A A M A A M Co-Act DNA A Basal transcription complex M A Inactive P Rep M A M M P Rep M M Repressed M M Rep Rep M M A ? M M Rep M M Rep M M M Demethylation HDM Methylation (activating) HMT HDM M M C Demethylation HMT Methylation (repressing) M H3 M K9 M M S1 0 K4 A P Acetylation (activating) HAT Deacetylation HDAC 4 K1 A 8 K1 A K23 A K27 S28 K36 M P K79 Histone tail Phosphorylation (activating) PK Dephosphorylation PP 260 .

on associated gene promoters while antagonizing the repressive modification—methylation of lysine 9 on histone H3 (H3K9) and its subsequent recruitment of HP1 (heterochromatin protein 1. active. even this is an oversimplification.8:355-367.6 For example. as methylated H3K9 is often found in the coding region downstream of a gene promoter and may be involved in transcriptional elongation.6 Additionally. see below). In gene promoter regions for example. or trimethylated states. K. KMT1C (G9a). methylation of different histone lysine residues can exert opposite effects on transcription. Nat Rev Neurosci. 2009 Class I and Class II enzymes. The amino (N) termini of the histones face outward from the nucleosome complex. H2B. trimethylation of H3K4 is highly associated with gene activation. which have not yet been identified with certainty. and phosphorylation (P) at several amino acid residues. There are several nuclear protein kinases and protein phosphatases known to regulate histone phosphorylation. Epigenetic regulation in psychiatric disorders. serine residue. and inactive). 6 Since phosphorylation at H3S10 recruits a HAT. as stated earlier. HMTs and HDMs also have activity towards nonhistone proteins.6 HMTs and HDMs not only discriminate between various histone lysine residues. but each enzyme is also unique in its ability to catalyze mono-. and histone demethylases (HDMs) remove them (Figure 1).20 Furthermore. and the dopamine and cyclic-AMP regulated protein phosphatase inhibitor. C. H3 phosphoacetylation commonly involves phosphorylation of S10 and acetylation of K14. Like HATs and HDACs. Renthal W. Summary of common covalent modifications of H3. are elegant examples shown to regulate H3S10 phosphorylation in the adult brain in response to cocaine exposure. 2007. S. which include acetylation. However. heterochromatin where all gene activity is permanently silenced (bottom left). di-. lysine methylation (which can be either activating or repressing) is catalyzed by histone methyltransferases (HMTs) and reversed by histone demethylases (HDMs). and have been implicated in the regulation of lifespan and metabolism. enabling each state to recruit unique coregulators and exert distinct effects on transcriptional activity. B. lysine residue. Kumar A. euchromatin (top left) in which histone acetylation (A) is associated with opening the nucleosome to allow binding of the basal transcriptional complex and other activators of transcription. This modification stabilizes the HAT. histone methylation provides each cell with exquisite control over an individual gene’s activity through numerous combinatorial possibilities.18 One of the best-characterized histone phosphorylation sites is serine 10 on histone H3 (H3S10). In reality. whereas trimethylation of H3K9 or H3K27 is repressive. or trimethylation or demethylation at that site. Histone methyltransferases (HMTs) add methyl groups to specific lysine residues of histones. repressed (bottom right). di-. methylation.19. a process called phosphoacetylation that further potentiates gene activation. KMT1A (SUV39H1).5 The repression caused by trimethylation of H3K9 is mediated in part via the recruitment of corepressors. Nestler EJ. permissive (top right). such as HP1. From ref 8: Tsankova N. or condensed.16 The individual functions of each HDAC remain an active topic of investigation. Picture of a nucleosome showing a DNA strand wrapped around a histone octamer composed of two copies each of the histones H2A. chromatin exists in a continuum of functional states in between (eg. and phosphorylation is catalysed by protein kinases (PK) and reversed by protein phosphatases (PP). No. Thus. Histone phosphorylation Histone phosphorylation is generally associated with transcriptional activation. H3 and H4. 3 . DARRP-32. 261 . although this remains uncertain.6 The mitogen-activated protein kinase. is specific for histone H3K9 but only adds 1 or 2 methyl groups. GCN5.Chromatin regulation in drug addiction and depression .Renthal and Nestler Dialogues in Clinical Neuroscience . Histone methylation Histone methylation generates unique docking sites that recruit transcriptional regulators to specific gene loci. or as inactive. or open. histone phospho- rylation likely plays an important role in the regulation of brain function.15 Class III HDACs (also referred to as sirtuins) are mechanistically distinct from the other HDACs.17. Enrichment of histone modifications such as acetylation and methylation (M) at histone N-terminal tails and related binding of transcription factors and coactivators (CoAct) or repressors (Rep) to chromatin modulates the transcriptional state of the nucleosome. Figure 1.21 Thus. Chromatin remodeling. A.Vol 11 . genetic disruption of the histone-modifying ability of MSK1 or DARRP-32 in vivo has dramatic effects on behavioral responses to cocaine. MSK1. Chromatin can be conceptualized as existing in two primary structural states: as active. with the distinct HMT. the neighboring lysine residue at H3K9 is often acetylated in concert with phosphorylation. the HMT. it can be observed on the promoters of immediate early genes such as c-fos when they are induced after cyclic adenosine monophosphate (cAMP) stimulation or glutamate treatment in cultured striatal neurons. Histone methylation occurs on lysine residues in mono-.6. Acetylation of lysine residues is catalysed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs). Recent evidence suggests that inactivated chromatin may in some cases be subject to reactivation in adult nerve cells.

This is likely.32 two genes known to play a critical role in cocaine-related behaviors. yet to be identified genes as well. such as MeCP2. can demethylate 1 or 2 methyl groups on H3K9. these enzymes establish and maintain the unique methylation patterns that exist within each cell type. While the regulation of these enzymes in brain remains unclear.27 suggesting that the context in which DNA methylation occurs is an important factor in its ultimate effect on transcription. and DNMT3b.35. for genes at which CREB is necessary to initiate transcription. KDM3A (JHDM2a). Mutations in MeCP2 cause the autistic spectrum disorder. Thus.31 The process by which repeated drug experimentation transitions into a chronically addicted state is the focus of intense research. eg.22. recent studies of MeCP2 indicate it may also serve to activate gene activity under some circumstances. controls dendritic spine density and is mutated in patients with mental retardation. For example. large complexes of enzymes are required to move between the unmethylated and fully trimethylated states. tissue-specific gene expression. Epigenetic mechanisms in drug addiction Drug addiction is a chronic relapsing disorder where motivation to seek and take drugs of abuse becomes compulsive and pathological. The first studies to implicate changes in chromatin structure in responses to drugs of abuse found that acute administration of cocaine rapidly increased histone H4 acetylation on the immediate early genes c-fos and fosB in striatum. a fundamental cellular process required for development. which are also observed in response to environmental enrichment and tests of learning and memory.30 Nevertheless. The exciting new possibility that druginduced alterations in chromatin structure may contribute to long-lasting behavioral changes provides a new avenue for novel therapeutics that improve drug rehabilitation.24 DNA methylation is thought to repress gene expression by interfering with the binding of transcription factors to their target sequences or by initiating the recruitment of corepressors. which. and genetic imprinting. illustrating the importance of DNA methylation in normal brain development. however.23 DNA methylation DNA methylation refers to the enzymatic methylation of cytosine bases. when methylated. despite several control gene promoters where acute cocaine does not affect histone acetylation. DMNT2 was recently shown to methylate RNA rather than DNA.36 may be accounted for by high levels of acetylation on specific subsets of genes. and histone H3 phosphoacetylation in striatum. a repressive histone modification. which occurs even after long periods of drug abstinence and is a major clinical challenge for successful treatment. Proper balance of histone methylation has already been strongly implicated in normal brain function. methylation at this site is repressive.Tr a n s l a t i o n a l r e s e a r c h catalyzing trimethylation of this site. the HDM. prevents the transcription factor CRE-binding protein (CREB) from binding. which can then recruit and stabilize transcriptional corepressors such as HDACs on specific gene promoters.38 262 .19. KDM4D (JMJD2D) to fully demethylate the trimethylated state. to name a few examples.33 The histone acetyltransferase CBP appears to be required for the drug-induced acetylation of the fosB promoter. Rett syndrome. and probably many other. DNMT3a. an acute cocaine dose increases total levels of histone H4 acetylation. as the HDM. the cAMP-response element (CRE) contains a cytosineguanine dinucleotide in the middle of its consensus sequence. remains unclear because.25 Thus. regulation of DNA methylation by environmental stimuli remains an attractive mediator of long-lasting changes in transcription in adult neurons.34 Interestingly. Methylated DNA can also recruit methyl-binding domain-containing proteins. as clues into these mechanisms may help better manage or perhaps fully treat addicted patients. X-inactivation. Similarly. There are three known enzymes which catalyze DNA cytosine methylation: DNMT1.29 The mechanism by which this occurs.32 These global increases in histone acetylation. are also observed after cocaine exposure37 and appear to occur on unique subsets of genes. the existence of DNA demethylases remains controversial.26 While there is a strong correlation between methylated DNA and repressed gene activity. as measured by Western blotting. requiring a distinct demethylase. unlike other chromatin modifications. as global increases in histone K9 methylation. Another avenue of intense research focuses on the mechanisms driving drug relapse. pharmacological inhibition of DNA methylation in the brain in vivo results in rapid demethylation of specific gene targets and severe deficits in learning and memory. KMT5C (SMCX).28 Together.

This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. 2009 The promoters of certain genes induced by chronic cocaine exposure are hyperacetylated for days to weeks after the last drug exposure (Figure 2). bdnf (brain derived neurotrophic factor). Cocaine promotes H3 phosphorylation via a distinct pathway. These findings suggest a role of histone acetylation in the maintenance of gene expression involved in drug addiction.39 Moreover. KMT1C/G9a. Chronic exposure to psychostimulants increases glutamatergic stignaling from the prefrontal cortex to the NAc. which through MSK1 can phosphorylate CREB and histone H3 at serine 10. Nat Rev Neurosci. Epigenetic regulation in psychiatric disorders. This causes DARPP32 to accumulate in the nucleus and inhibit protein phosphatase-1 (PP1) which normally dephosphorylates H3. CREB binding protein (CBP) to acetylate histones and facilitate gene activation. Kumar A. This repression of c-fos also involves increased repressive histone methylation. Cocaine-induced alterations in chromatin structure in the nucleus accumbens (NAc). altered expression of each of these genes has been shown to contribute to the addiction behavioral phenotype.Vol 11 . FosB is also upregulated by chronic psychostimulant treatments. This includes the cAMP response element binding protein (CREB). Regulation of chromatin structure by drugs of abuse. It is not yet known how cocaine regulates histone demethylases (HDM) or DNA methyltransferases (DNMTs). whereby PKA activates protein phosphatase 2A. cdk5) and repress others (eg. and is known to activate certain genes (eg. In addition. For example. 263 . the phosphorylation of which induces its association with the histone acetyltransferase. From ref 8: Tsankova N. which is thought to occur via the induction of specific histone methyltransferases (HMTs). Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling.Renthal and Nestler Dialogues in Clinical Neuroscience . 3 . the expression of cdk5 (cyclin-dependent kinase 5). which alters histone H3 methylation on K9. Renthal W.38 were found to be upregulated after chronic cocaine administration and their gene promoters hyperacetylated. These drugs increase cAMP levels in striatum. which.Chromatin regulation in drug addiction and depression . Nestler EJ. which activates protein kinase A (PKA) and leads to phosphorylation of its targets. in addition to phosphorylating CREB. Drug-induced signaling events are depicted for psychostimulants such as cocaine and amphetamine. BDNF. among many other genes. This results in nuclear export of HDAC5 and increased histone acetylation on its target genes (eg. c-fos) where it recruits HDAC1 as a corepressor. have been shown to regulate behavioral responses to Cocaine/amphetamine Cytoplasm HDMs? DNMT? CaMK P HDAC 5 cAMP MAPK/ERK PKA RSK/MSK1 CaMK Nucleus HMT DARPP32 PP1 + HDAC 5 + P CREB CBP + HDAC 1 ΔFosB P CREB CBP P H3–S10 + Cdk5. NK1R [NK1 or substance P receptor]).39 and sirt1 and sirt2 (two subtypes of sirtuins).32 npy (neuropeptide Y). 2007. including drug withdrawal and relapse. NPY A NK1R A FosB A M c-F os A Figure 2. also phosphorylates HDAC5. the ventral portion of striatum heavily implicated as a brain reward region. cocaine regulates the HMT. Cocaine also activates the mitogen activated protein kinase (MAPK) cascade. No.8:355-367. while egr-1 (early growth response 1) was found to be downregulated and hypoacetylated after cocaine withdrawal. leading to the dephosphorylation of serine 97 of DARPP32.

Unfortunately. results in less sensitivity to cocaine. CBP. permitting hyperacetylation of histones at target genes for HDAC5 (Figure 2). anhedonia. global histone methylation of H3K9 is also regulated by cocaine and. and methylation in mediating expression changes in specific sets of genes that are crucial for controlling behavioral responses to drugs of abuse. alters behavioral responses to the drug. these findings implicate changes in histone acetylation.41 Conversely.19.40 This phosphorylation reaction may be mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII). but it may involve experimental differences with the self-administration paradigm or the HDAC inhibitor used.43 The explanation for these different observations is unclear. significantly potentiates the locomotor-activating and rewarding responses to cocaine. in turn. Chronic cocaine administration increases the phosphorylation of HDAC5 and shuttles it out of the nucleus.37 Overall. in general. or related antidepressants. whose expression is regulated in the NAc by chronic cocaine administration. trichostatin A.40. KMT1C (G9a). and weight changes. reducing histone acetylation by overexpressing certain HDACs. attenuates it. 32. less than 50% of patients exhibit a complete response to SSRIs. thus leaving a substantial portion of depressed 264 . as mice lacking this kinase have attenuated locomotor responses to cocaine. The genes at which histone phosphorylation is occurring in response to cocaine remain poorly defined with an exception of c-fos. Cocaine alters histone acetylation through many enzymes in the NAc. For example. a process which requires the kinase MSK1. the protein then accumulates in the nucleus to inhibit protein phosphatase-1 from dephosphorylating histone H3. inhibition of a particular H3K9 histone methyltransferase.40 Thus. Pharmacological inhibition of HDACs in the NAc. advances are being made in identifying the individual gene promoters where chronic cocaine induces alterations in H3K9 methylation and thereby regulates gene expression in the NAc. drug experimentation to compulsive drug use). but become hypersensitive when treated with a chronic course of cocaine.40 Two reports have extended these findings in rat models of cocaine self-administration. where animals are trained to press levers to receive the drug. Cocaine-induced inhibition of protein phosphatase-1 also plays an important role in H3 phosphorylation in striatum (Figure 2). since inhibition of H3K9 methylation would also be expected to enhance gene activity. where dramatic histone phosphorylation occurs in conjunction with acetylation (phosphoacetylation). Global levels of histone H3 phosphorylation at serine 10 are induced by acute cocaine in striatum. Together. these data suggest that. potentiates drug-taking42 while delivery of the HDAC inhibitor. which increases histone acetylation in this brain region. Dopamine D1 receptor activation alters the phosphorylation of dopamine-regulated and cyclic-AMP-regulated phosphoprotein of 32kD (DARPP-32) at particular serine residues.32 The function of MSK1 is behaviorally important. Epigenetic mechanisms in depression Depression is a chronic disorder characterized by many debilitating symptoms including dysphoria. sodium butyrate. HDAC5.Tr a n s l a t i o n a l r e s e a r c h drugs of abuse. raising the interesting possibility that this HDAC is involved in the behavioral transitions which occur between acute and chronic cocaine exposure (eg. As well.32.34. of which selective serotonin reuptake inhibitors (SSRIs) or mixed serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most common. phosphorylation. mice deficient for HDAC5 display normal rewarding responses to initial cocaine exposures. potentiates behavioral responses to the drug. Consistent with its regulation by cocaine. or knockdown of the HAT. Most people diagnosed with depression are prescribed some type of antidepressant medication. pharmacological and genetic manipulations that increase histone acetylation appear to potentiate behavioral responses to cocaine and suggest that altered histone acetylation may contribute to establishment of an addicted state. sleep disturbances. Interestingly. delivery of the HDAC inhibitor. but one particular HDAC. 37 These findings are consistent with histone acetylation findings. SNRIs. increases in gene expression potentiate behavioral sensitivity to drugs of abuse. responds uniquely to chronic cocaine administration. As mentioned earlier. since ex vivo inhibition of CaMKII reduces the activity-induced phosphorylation of HDAC5. Histone H3 phosphorylation and phosphoacetylation also appear to play key roles in drug-regulated behaviors.20 The simultaneous activation of an H3 kinase and inhibition of an H3 phosphatase results in the robust increase in H3 phosphorylation after acute cocaine exposure.

fluoxetine.46 Indeed. and loss of interest in social interaction. No. LSD1) than it is of either monamine oxidase A or B. overexpression of HDAC5 in the hippocampus blocks the behavioral effects of chronic antidepressant treatment.46 Brain derived neurotrophic factor (BDNF) plays a critical role in the development of the social defeat phenotype and its reversal by antidepressant treatment. While these inhibitors target numerous HDACs. stood out because it was oppositely regulated by stress and antidepressant treatment. After 10 days of social defeat. tranylcypromine. that remains hypermethylated on the bdnf promoter within hippocampus for at least a month after defeat stress. Importantly. Each day the stress begins as a brief physical encounter (typically 5 to 10 minutes) followed by a full day of sensory contact (eg. H3K27 remains hypermethylated. making chronic social defeat stress an attractive model in which to study the molecular adaptations associated with a depressed-like state and those involved with antidepressant action. which may serve as novel targets for more effective therapeutics.46 Interestingly. some of the major symptoms such as anhedonia and sleep and weight disturbances. One of the most challenging obstacles for depression research has been the development of an animal model that accurately recapitulates human depression. Psychiatric research is thus focused on identifying new mechanisms that are involved in the pathogenesis and maintenance of depression. the experimental mice develop a chronic syndrome (lasting more than a month) that is characterized by anhedonia.47 Thus. anxiety-like symptoms. The pathogenesis of depressed-like states is typically modeled in rodents by chronic exposure to stress. is actually a much stronger inhibitor of the histone H3K4 demethylase KMT1A (formerly. which are associated with gene activation. involves the repeated exposure of an experimental mouse to a series of aggressive mice over 10 days. which inhibits monoamine oxidases and is used as an antidepressant. smell. Why do certain mice 265 . HDAC inhibitors demonstrated antidepressant-like prosperities. While chronic antidepressant treatment of mice exposed to chronic social defeat ameliorates many of the behavioral deficits and restores bdnf mRNA to normal levels. suicide). weight loss. Arguing against this interpretation is the knowledge that several structurally unrelated monoamine oxidase inhibitors. suggesting that increased histone acetylation on the bdnf promoter is a key mechanism to overcome the repressive effects of H3K27 methylation.46 A mechanism for this long-lasting regulation of gene expression was identified as methylation of H3K27. The maintenance of H3K27 methylation even after chronic antidepressant treatment suggests that BDNF expression might revert to a repressed state if drug adminis- tration were stopped.Renthal and Nestler Dialogues in Clinical Neuroscience . and their reversal by antidepressant treatment.48 This was especially apparent when an HDAC inhibitor was administered in addition to an SSRI. Indeed. a repressive histone modification. The increase in H3 acetylation by antidepressant treatment suggested that HDAC inhibitors may also have antidepressant-like effects. which have not been shown to inhibit histone demethylases. and that chronic antidepressant treatment reversed this downregulation. HDAC5. The recovery of bdnf expression after antidepressant treatment is likely mediated by the antidepressantinduced increase in histone H3K4 methylation and H3 polyacetylation in hippocampus. are still effective antidepressants. 3 . While no model can effectively model all aspects of human depression (eg.44 One such model. sight) as the mice are separated by a screen. It was observed that mice susceptible to defeat stress show significantly higher firing rates of dopaminergic neurons in the ventral tegmental area (VTA) after stress exposure compared with resilient mice. can be studied in rodents.Chromatin regulation in drug addiction and depression . It was observed that BDNF in the hippocampus is downregulated for at least 1 month after chronic social defeat stress. it will be interesting to determine whether any of the antidepressant properties of tranylcypromine derive from its blockade of KMT1A and the subsequent facilitation of H3K4 methylation. chronic social defeat stress.Vol 11 . virtually genetically identical) mice. SSRIs or SNRIs reverse most of these behavioral end points. These resilient mice had normal VTA firing rates because of a stress-induced upregulation of potassium channels in this brain region. which was proposed as a form of “molecular scar. This novel epigenetic mechanism. one specific isoform.46.” may describe a potential mechanism by which the symptoms of depressed patients reappear after cessation of antidepressant treatment. Another intriguing aspect of chronic social defeat stress is that the severity of the depression-like phenotype varies within a cohort of inbred (ie. 2009 patients with a chronic syndrome for which few effective clinical alternatives are available.45. this remains speculative and further research is needed. in both the chronic social defeat model and in the forced swim test. however.

genome-wide. they are among the best evidence to date implicating epigenetic mechanisms in anxiety and stress and suggest that DNA methylation at the GR gene promoter (and probably other genes) in both rats and humans may contribute to this phenomenon. new advances in high-throughput sequencing are enabling such characterization of chromatin regulation and gene expression.8:140-146. these studies have been translated from rats into humans by studying the hippocampus of patients who committed suicide with or without a history of child abuse. Curr Opin Genet Dev. Luger K. Renthal W. 4. 5. Early insight into the role of DNA methylation in behavior followed from studies of maternal care that clearly demonstrate an experiencedependent rather than genetic basis for how rats treat their offspring. at an incredible rate and resolution. Harbison CT. Nature. Treatment with an HDAC inhibitor not only reduced DNA methylation on the GR receptor gene but also improved anxiety and stress responses in these rats. Hayashi K. While the precise signaling mechanisms by which environmental stresses converge on chromatin are still under investigation (eg. Armed with these and other new research tools. Ultimately though.50 While these data do not demonstrate causation. Perceptions of epigenetics. it was observed that DNA methylation on the GR gene promoter was significantly higher. While extremely exciting. Meaney and colleagues identified a region of the glucocorticoid receptor (GR) gene. 2. and provide new avenues for the development of more effective antidepressants. Felsenfeld G. these studies demonstrate that chromatin structure is an important substrate for long-lasting changes in behavioral responses to stress and antidepressant treatments. 2007.403:41-45. Taken together. these early studies suggest the exciting possibility that pharmacological manipulation of chromatin remodeling pathways could be a novel approach to new antidepressant development. Nat Rev Neurosci. 2007. a chronically addicted or depressed state.122:517-527. Nature. and may soon prove to be a major avenue for novel therapeutics. Another important epigenetic mechanism that may contribute to long-lasting changes in neural function and behavior is DNA methylation. which was hypermethylated throughout adulthood in rats who received poor maternal care. Kouzarides T. 266 . Chromatin modifications and their function. Rats that receive poor maternal care as pups grow up to become poor mothers to their pups. et al. which life experiences trigger these chromatin remodeling events? These are important questions that may shed fundamentally new light onto an extraordinarily complex syndrome. Surani MA. Li B. 2005. 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disturbances in working memory.1 For a disorder such as schizophrenia. the disease process appears to result from a complex interplay of an unknown number of genetic liabilities and environmental risk factors that unleash pathogenetic mechanisms which produce a pathological entity. 3811 O’Hara Street. MD. © 2009. are present in a milder form in individuals at genetic risk who do not become clinically ill. Department of Psychiatry. These pathological changes so alter the normal function of the affected circuits that the resulting pathophysiology gives rise to the emergent properties recognized as the clinical features of the illness. The altered activation of the DLPFC under such conditions might be specific to the disease process of schizophrenia because these disturbances are present in medication-naïve individuals with schizophrenia. This article reviews disturbances in excitatory and inhibitory components of DLPFC circuitry from the perspective of developmental neuroplasticity and discusses their implications for the identification of novel therapeutic targets. but not in subjects with other psychotic disorders or major depression. W1651 BST. Pittsburgh. working memory Author affiliations: Departments of Psychiatry and Neuroscience. Lewis. PA 15213. are accompanied by altered activation of the dorsolateral prefrontal cortex (DLPFC. MD Schizophrenia is a neurodevelopmental disorder characterized by deficits in cognitive processes mediated by the circuitry of the dorsolateral prefrontal cortex (DLPFC).11:269-280. glutamate. are relatively stable over the course of the illness. For example.org N 269 . a conserved set of molecular and cellular disturbances in specific neural circuits. University of Pittsburgh.2 One approach to dissecting this disease process involves focusing on a well-defined clinical component of the illness.3 and are the best predictor of long-term functional outcome. B).6 www. the ability to transiently maintain and manipulate a limited amount of information in order to guide thought or behavior. Keywords: GABA. All rights reserved europlasticity can be broadly considered to be the capacity of the brain to change the molecular and structural features that dictate its functions in response to a disease process (or other factors) that disrupts those functions. are independent of the psychotic symptoms of the disorder.dialogues-cns. 2009.edu) Copyright © 2009 LLS SAS. prefrontal cortex. Figure 1 A. deficits in cognitive abilities are thought to be the core features of schizophrenia because they occur with high frequency in individuals with schizophrenia.Tr a n s l a t i o n a l r e s e a r c h Neuroplasticity of excitatory and inhibitory cortical circuits in schizophrenia David A. Pennsylvania. LLS SAS Dialogues Clin Neurosci. USA Address for correspondence: David A. Lewis. These deficits are associated with a range of alterations in DLPFC circuitry. some of which reflect the pathology of the illness and others of which reflect the neuroplasticity of the brain in response to the underlying disease process.4 Of the domains of cognition affected in schizophrenia.5. University of Pittsburgh. USA (e-mail: lewisda@upmc.

Axons that project to the DLPFC from other brain regions also tend to innervate different subsets of cortical layers. A) Photograph of an unstained coronal block. Pyramidal neurons (red) represent about 75% of cortical neurons and typically have triangularly-shaped cell bodies. C) Schematic representation of neurons across cortical layers. Neuropsychopharmacology. Neuroplasticity of neocortical circuits in schizophrenia.33:141-165. Copyright © Nature Publishing Group 2008 270 . Each mediator is considered from the perspective of which alterations reflect the disease process and which might be neuroplastic responses of the affected circuits. This block also includes the adjacent anterior cingulate gyrus (ACG) of the limbic lobe. the axons of pyramidal neurons preferentially provide excitatory projections to different brain regions. a single apical dendrite directed towards the pial surface. axonal projections (green) from the thalamus terminate in layers deep 3 and 4. For example. Reproduced from ref 1: Lewis DA. These neurons use the inhibitory neurotransmitter GABA. cut immediately anterior to the corpus callosum through the left hemisphere of a postmortem human brain. The remaining ~25% of DLPFC neurons are local circuit or interneurons (blue). Depending on their laminar location. 2008. and an array of basilar dendrites. Although addi- A Dorsolateral B 1 2 C Apical dendrites 3 V e n t r o m e d i a l Orbital 4 5 Basilar dendrites 6 White matter Contralateral ipsilateral Striatum or brain stem Thalamus Figure 1. existing data suggests that many of the alterations described below are probably also present in other cortical regions that are dysfunctional in schizophrenia. numbered from the pial surface of the cortex to the underlying white matter. and have axons that arborize locally and innervate other neurons in the same area of the prefrontal cortex. B) Nissl-stained section showing the typical appearance of six layers or lamina. based on the size and packing density of neurons.8.9 NMDA receptor antagonists such as phencyclidine (PCP) or ketamine increase both positive and This review examines alterations in components of excitatory and inhibitory neurotransmission in DLPFC circuitry that might contribute to the impairments in working memory in schizophrenia.7 Neuroplasticity of excitatory cortical connections in schizophrenia Excitatory connections in the DLPFC are altered in schizophrenia The disease process of schizophrenia appears to involve deficient glutamate-mediated excitatory neurotransmission through the N-methyl-D-aspartic acid (NMDA) receptor. Gonzalez-Burgos G. The portion of the dorsolateral prefrontal cortex (DLFPC) delineated by the small rectangle is shown at higher magnification in panel B. containing the prefrontal cortex.Tr a n s l a t i o n a l r e s e a r c h Selected abbreviations and acronyms CCK DLPFC GABA GAD GAT NMDA PV cholecystokinin dorsolateral prefrontal cortex γ-aminobutyric acid glutamic acid decarboxylase GABA membrane transporter N-methyl-D-aspartic acid parvalbumin tional studies are required.

18 Consistent with this interpretation. has been reported to be decreased in the DLPFC of subjects with schizophrenia.32. Although the number of these neurons does not appear to be altered in schizophrenia.25. iii) this pattern of alterations is not restricted to the DLPFC.Lewis Dialogues in Clinical Neuroscience . the mean somal size of all layer 3 neurons in DLPFC area 9 was smaller in subjects with schizophrenia.26 Studies of basilar dendritic spine density on Golgi-impregnated pyramidal neurons in each cortical layer of the DLPFC in the same cohort of subjects found a significant effect of diagnosis on spine density only for pyramidal neurons in deep layer 3 (Figure 2).10 In addition. systemic administration of NMDA receptor antagonists disrupts working memory in rats. 17 Increased cell packing density has been interpreted as evidence of a reduction in the amount of cortical neuropil.27 The functional integrity of the pyramidal neurons with lower dendritic spine densities may be reflected in changes in their somal volume. synaptophysin protein. pyramidal neurons were smaller in schizophrenia. the axon terminals. suggesting that other components of NMDA receptor signaling might be affected in the illness. many pyramidal cells in layers 2 to 3 send axonal projections to other cortical regions. and pyramidal neurons in layer 6 furnish projections primarily to the thalamus. these findings suggest that in schizophrenia: i) basilar dendritic spine density is lower and somal volume is smaller in deep layer 3 pyramidal neurons. as well as the targets of the majority of glutamate-containing axon terminals. the mean somal volume of Nisslstained pyramidal neurons in DLPFC deep layer 3 was also 9% smaller in a different cohort of subjects with schizophrenia.25. Reduced excitatory connections in schizophrenia are specific to a subset of pyramidal neurons Pyramidal neurons can be divided into subgroups based on the brain region targeted by their principal axonal projection and the sources of their excitatory inputs.31 Furthermore. shifts in somal size may indicate disturbances in neuronal connectivity. somal volumes of deep layer 3. 12 However. and iv) these differences reflect the underlying disease process and not confounding factors.25 Consistent with this observation. gene expression profiling studies have found reduced tissue levels of gene transcripts that encode proteins involved in the presynaptic regulation of neurotransmission. No. and the administration of subanesthetic doses of ketamine to healthy individuals produces thought disorder and other features similar to those seen in schizophrenia. both of these characteristics are associated with the location of pyramidal cell bodies in different layers of the cortex (Figure 1C). dendritic spine density in pyramidal neurons has been reported to be lower in the DLPFC 24.22 Dendritic spines are the principal targets of excitatory synapses to pyramidal neurons. In schizophrenia. ii) these alterations are specific to or at least most prominent in deep layer 3. given that somal size has been shown to be correlated with measures of a neuron's dendritic tree28 and axonal arbor. and glial processes that occupy the space between neurons. but not of layer 5.30 Similarly.29 Indeed. dendritic spines.23 they are subject to a number of neuroplastic changes.Vol 11 .16 neuronal density in the DLPFC has been reported to be increased in schizophrenia.11 and application of an NMDA receptor antagonist to the DLPFC impairs working memory performance in monkeys. pyramidal neurons in layer 5 tend to project to the striatum and other subcortical structures. such as a loss of their presynaptic excitatory input. For example. Although most dendritic spines present are stable in number during adulthood. In the DLPFC. For example.14 Anatomical studies do support the presence of inputspecific alterations of excitatory connections in the DLPFC in schizophrenia. 271 . and was accompanied by a decrease in the density of the largest neurons in deep layer 3. without a change in somal volume in layer 5. the mean cross-sectional somal area of the Golgi-impregnated. deep layer 3 pyramidal neurons was 9% smaller in the subjects with schizophrenia relative to normal control subjects.13 such findings for mRNA and protein levels of NMDA receptor subunits in the DLPFC have been limited in magnitude and not always replicated. pyramidal neurons (Figure 1C) are the principal source of glutamate neurotransmission. transcription. in another study. although postmortem studies have reported alterations in measures of glutamate receptor binding.19-21 Furthermore. understanding the nature of these neuroplastic responses requires knowledge of the specific circuits that are affected and the developmental mechanisms that might underlie these changes. in both primary and association auditory cortices. and subunit protein expression in several brain regions in subjects with schizophrenia. 2009 negative symptoms in patients with schizophrenia.Cortical neuroplasticity in schizophrenia .33 Together.15. 3 . a marker of axon terminals.

006 0.3 0.5 Mean spine density (spines/µm) 0.4 0.08 16% 272 .Tr a n s l a t i o n a l r e s e a r c h A Dendritic spine B C D 0.6 Deep layer 3 F2.003 23% 0 Control Schizophrenia Subject group Psychiatric P=.01. P=.1 P value NS .003 NS NS P=.37=6.2 E Layer Superficial 3 Deep 3 Layer 5 Layer 6 Change in Schizophrenia -13% -23% +3% +12% 0.

39 Interestingly. a protein responsible for reuptake of released GABA into nerve terminals. Subclasses of cortical GABA neurons can be distinguished on the basis of a number of molecular. and thereby forestall the appearance of the clinical features of the illness until synapse number falls below some critical threshold.46 Thus.45 Thus. A) Schematic diagram illustrating the dendritic tree and dendritic spines on a prototypic pyramidal neuron. the late developmental refinements in excitatory connectivity are more marked in layer 3 than in the deeper cortical layers. pruned synapses are functionally immature.16. on the functional properties of the synapses that are pruned.36 suggesting that they may be associated with the apparent laminaspecific alterations in spine density in schizophrenia. and that some other factor. Copyright © Nature Publishing Group 2008 273 .22. expression of the mRNA for the GABA membrane transporter (GAT1). these data suggest that the substantial remodeling of excitatory connectivity of the primate DLPFC during adolescence primarily involves the elimination of mature synapses. such alterations in synaptic protein expression might disturb the mechanisms of adolescence-related synapse elimination leading.37 In humans. for instance. Immature glutamate synapses are relatively weak and their maturation involves an activity-dependent increase in strength. B) Electron micrograph showing a dendrite (D) with two spines (S). the expression of GAD67 mRNA was not detectable in ~25% to 35% of GABA neurons in layers 15 of the DLPFC. Neuropsychopharmacology.47-52 At the cellular level. recent findings in the developing monkey DLPFC indicate that the excitatory inputs to layer 3 pyramidal neurons mature functionally during the age range when they are present in high density and before synaptic pruning begins.Cortical neuroplasticity in schizophrenia .38. The observation of alterations in the expression of certain synaptic proteins in schizophrenia suggested the possibility that the exuberant synapses present before adolescence somehow compensated for a dysfunction in excitatory transmission in individuals with schizophrenia. During early brain development. somehow tags mature synapses for pruning. D) Scatter plot demonstrating the lower density of spines on the basilar dendrites of deep layer 3 pyramidal neurons in the DLPFC of subjects with schizophrenia relative to both normal and psychiatrically-ill comparison subjects.47 Similarly. No. was decreased in a similar minority of GABA neurons.36. 2008. electro- Figure 2. but the remaining GABA neurons exhibited normal levels of GAD67 mRNA.53 These findings suggest that both the synthesis and reuptake of GABA are lower in a subset of DLPFC neurons in schizophrenia.Lewis Dialogues in Clinical Neuroscience .33:141-165. the presence of functionally mature synapses prior to adolescence supports the hypothesis that the excess in excitatory synapse number prior to adolescence might be able to compensate for a molecular based dysfunction of these synapses in individuals with schizophrenia.Vol 11 . Each spine receives an asymmetric (presumably excitatory) synapse from an axon terminal (at).44 However. this synaptic pruning is thought to underlie the decrease in cortical gray matter thickness that occurs during adolescence.41. 2009 The contribution of developmental plasticity to dendritic spine alterations in schizophrenia Dendritic spine density on DLPFC layer 3 pyramidal neurons undergoes a substantial decline during adolescence in primates. and thus mark for elimination the immature synapses that are not strengthened. the principal synthesizing enzyme for γ-aminobutyric acid (GABA). Such activity-dependent strengthening might underlie synapse stabilization. in part. such as the neuronal source of input.16. Reproduced from ref 1: Lewis DA. Neuroplasticity of neocortical circuits in schizophrenia. Pyramidal neuron dendritic spines in the human DLPFC. 3 . Note the reduced density of spines in the subjects with schizophrenia in these extreme examples.34 Consistent with the findings that dendritic spines are the main site of excitatory synaptic input onto pyramidal cells and that all mature dendritic spines contain an excitatory synapse.42 The potential contribution of excitatory synapse pruning during adolescence to disease-related changes in DLPFC function depends. 35 the number of excitatory synapses declines in a similar age-related fashion in both monkey and human DLPFC. to excessive synapse pruning and decreased spine number in the illness.43. in the DLPFC of subjects with schizophrenia. Gonzalez-Burgos G.40 Neuroplasticity of inhibitory cortical connections in schizophrenia Prefrontal inhibitory neurotransmission is altered in schizophrenia Studies from multiple laboratories have consistently found lower levels of the mRNA for the 67 kilodalton isoform of glutamic acid decarboxylase (GAD67).40 Alternatively. C) Golgi-impregnated basilar dendrites and spines on deep layer 3 pyramidal neurons from a normal comparison (top) and two subjects with schizophrenia (bottom). E) Laminar-specificity of the spine density differences in the same subjects.

the enhanced facilitation of GABA release from fast-spiking neurons with reductions in PV is associated with increased power of gamma oscillations 63 (which is.70 274 . which comprise ~25% of GABA neurons in the primate DLPFC. PV decreases the residual Ca2+ levels that normally accumulate in nerve terminals and facilitate GABA release during repetitive firing. GAT1 immunoreactivity is selectively reduced in the characteristic axon terminals (cartridges) of PV-containing chandelier neurons.63 Furthermore. but not in layers 2 and 5.51 In the cortex. immunoreactivity for the GABAA receptor α2 subunit (which is present in most GABAA receptors in this location 59) is markedly increased in schizophrenia.57 In contrast. 58 In the postsynaptic targets of these axon cartridges. deficient in schizophrenia). and the upregulation of postsynaptic GABAA receptors.47.57 In the DLPFC of subjects with schizophrenia. For example.Tr a n s l a t i o n a l r e s e a r c h physiological. Thus. other findings indicate that alterations in PVcontaining GABA neurons cannot account for all of the observed findings in postmortem studies of schizophrenia. 70 Because activation of the CB1R suppresses GABA release from the terminals of CCK neurons. parvalbumin (PV). in addition. Similarly. the ~50% of GABA neurons that express the calcium binding protein calretinin appear to be unaffected.55 (Figure 3). the axon terminals of CCK-containing large basket neurons. appear to represent neuroplastic responses that might act synergistically to increase the efficacy of GABA neurotransmission at pyramidal neuron axon initial segments during the types of repetitive neuronal activity associated with working memory. it is possible that compensation at chandelier cell synapses is not effective because additional interneuron subclasses are also functionally deficient in schizophrenia. 61. approximately half of PV mRNA-containing neurons lack detectable levels of GAD67 mRNA. the affected GABA neurons in schizophrenia include the subclass that contain the calcium-binding protein. 68 Interestingly. of pyramidal neurons54. contain type I cannabinoid receptors (CB1R). the combined reduction of PV and GAT1 proteins in chandelier cell axon cartridges. the resulting prolongation of IPSCs increases the probability of IPSC summation.53 even though the density of PV neurons is much greater in layers 3 and 4 than in layers 2 and 5. as explained below. and thereby augments GABA signaling. PV mRNA expression was reduced in layers 3 and 4. of Ca2+ transients in GABA nerve terminals. The upregulation of the postsynaptic GABA A receptors that contain α2 subunits would be expected to increase the efficacy of the GABA that is released from chandelier neurons.62 Thus. in subjects with schizophrenia.65 Consistent with this interpretation. the levels of GAD67 and GAT1 mRNAs are reduced to comparable degrees in layers 2-5. the downregulation of this receptor may represent a compensatory response to reduce the ability of endogenous cannabinoids to decrease GABA release from CCK/CB1R-containing axon terminals. PV-containing neurons include fast-spiking chandelier and basket neurons that principally target the axon initial segments and cell body/proximal dendrites. although the number of PV neurons appears to be unchanged56. and anatomical properties. which target selectively pyramidal neuron cell bodies. the axon initial segments of pyramidal neurons.69 and the mRNA and protein levels of CB1R are also lower in schizophrenia. but accelerates the decay. other studies have found lower tissue concentrations of the mRNAs for the neuropeptides somatostatin (SST) and cholecystokinin (CCK) in the DLPFC of subjects with schizophrenia (Figure 3). For example. enhances the total efficacy of IPSC trains.57 Indeed. 61. Alternatively. PV is a slow calcium buffer that does not affect the amplitude. SST is expressed by GABA neurons located in layers 2 and 5 that do not express PV or CR. For example. However. respectively.66 In addition.67 CCK is also heavily expressed in GABA neurons that do not contain either PV or SST located principally in layers 2-3 of the primate prefrontal cortex. In individuals with schizophrenia the expression level of PV mRNA is reduced. the blockade of GABA reuptake via GAT1 prolongs the duration of inhibitory postsynaptic currents (IPSCs) when synapses located close to each other are activated synchronously64.61 Studies in PV-deficient mice have demonstrated that a decrease in PV increases residual Ca2+ and favors synaptic facilitation.60 Several lines of evidence suggest that the reductions in presynaptic GABA markers (GAT1 and PV) and increased postsynaptic GABA A receptors are compensatory responses to a deficit in GABA release from chandelier neurons. the persistence of cognitive impairments in individuals with schizophrenia suggests that these neuroplastic changes in GABA neurotransmission from chandelier neurons are insufficient as compensatory responses.

Schematic summary of putative alterations in DLPFC circuitry in schizophrenia. Expression of the neuropeptide somatostatin (SST) is decreased in GABA neurons (dark blue) that target the distal dendrites of pyramidal neurons. Gene expression does not seem to be altered in calretinin (CR)-containing GABA neurons (red) that primarily target other GABA neurons (gray). J Clin Invest. Pyramidal neurons (light blue) in deep layer 3 have smaller somal size. Some studies indicate that the number and/or gene expression in oligodendrocytes is also altered.Lewis Dialogues in Clinical Neuroscience .119:706-716. 2009. suggest altered regulation of GABA neurotransmission in a subset of basket neurons (purple) that target the cell body and proximal dendrites of pyramidal neurons. Sweet RA. Putative alterations in thalamic and dopamine (DA) cell bodies and their projections to the DLPFC are also shown. Decreased cholecystokinin (CCK) and cannabinoid receptor 1 (CB1) mRNA levels. and lower CB1 protein in axon terminals.Cortical neuroplasticity in schizophrenia . Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. 3 . and a reduced axonal arbor in schizophrenia. Copyright © American Society for Clinical Investigation 2009 275 . lower dendritic spine density. Altered GABA neurotransmission by PV-containing neurons (green) is indicated by expression deficits in several gene products as well as by lower levels of GAT1 protein in the terminals of chandelier neurons and upregulated GABAA receptor α2 subunits at their synaptic targets. shorter basilar dendrites. the axon initial segments of pyramidal neurons (enlarged square).” solid arrows indicate abnormalities supported by convergent and/or replicated observations. Reproduced from ref 2: Lewis DA.Vol 11 . Not all of the circuitry alterations shown here have been sufficiently replicated or demonstrated to be specific to the disease process of schizophrenia to be considered established “facts. No. 2009 Figure 3.

79 Thus. disynaptic inhibition creates a time window during which the number of excitatory inputs required to evoke pyramidal neuron firing must occur. both chandelier and basket neurons target multiple pyramidal neurons.and postsynaptic markers of the functional properties of chandelier axon inputs to the axon initial segment (AIS) of pyramidal neurons exhibit a very protracted maturation. ankyrin-G- 276 . adult levels are achieved at 3 months postnatal. is localized to AIS. neurofascin.80 Thus.72 Second. First. For example. which is localized to the AIS of pyramidal neurons through its direct interaction with ankryin-G. The contribution of developmental plasticity to GABA neuron alterations in schizophrenia In the monkey prefrontal cortex DLPFC. GABAA receptors containing α2 subunits predominate in pyramidal neuron AIS especially in cortical layers 24. especially those containing α2 subunits.82 These findings indicate that both pre. formed by both chemical and electrical synapses. suggesting that the capacity to synchronize pyramidal neuron output in the prefrontal cortex (PFC) might be in substantial flux until adulthood. networks of PV-positive GABA neurons. are required for the formation and stabilization of GABA synapses at AIS86. synapses rises rapidly during the third trimester of gestation and perinatal period until stable. immunoreactivities for the calcium-binding protein PV and GAT1 in chandelier axon cartridges are not detectable or low at birth. gamma band oscillations in the human DLPFC increase in proportion to working memory load.71.55 The resulting feed-forward. give rise to oscillatory activity in the gamma band range.36 In contrast.81.and postsynaptic markers of GABA neurotransmission undergo significant changes during postnatal development. the density of symmetric. thalamic afferents) of excitatory input. PV-positive GABA neurons and pyramidal neurons share common sources (eg. resulting from impaired regulation of pyramidal cell networks by PV-positive GABA neurons. alterations in CCKcontaining basket cells could also contribute to impaired gamma oscillations in schizophrenia. Presynaptically. rise (albeit with different developmental time courses) to peak levels early in postnatal development that are sustained until ~15 months of age. may contribute to reduced levels of induced gamma band oscillations. or in the density of. and consequently to impairments in cognitive tasks that involve working memory in subjects with schizophrenia.82 Postsynaptically. the activity of DLPFC GABA neurons is essential for normal working memory function in monkeys. including complementary roles in regulating gamma band oscillations. axon terminals within chandelier axon cartridges.and PV-containing cells provide convergent sources of perisomatic inhibition to pyramidal neurons that play specific roles in shaping network activity. on how GABA synapses are stabilized at the AIS while the functional properties of GABA neurotransmission at this location are changing during postnatal development.75 Fourth. the synchronized firing of a neuronal population at 30 to 80 Hz.83 these changes in PV and GAT1 immunoreactivity are likely to reflect shifts in the concentration of these proteins rather than changes in the presence of. pre.34. prefrontal gamma band oscillations are reduced bilaterally during a working memory task. pyramidal neuron AIS contain specific proteins that regulate synapse structure and receptor clustering: i) Ankyrin-G.73 Third. at least in part.87 is a critical component in the organization and stabilization of membrane proteins at the AIS88.84 The density of pyramidal neuron AIS immunoreactive for α2 subunits is high at birth.82 Since chandelier cartridges are readily visualized with Golgi staining across postnatal development. then significantly declines during adolescence before achieving stable adult levels. presumably GABA. The significance of these changes depends.89 In monkey DLPFC. and then rapidly decline during adolescence until stable adult levels are achieved.Tr a n s l a t i o n a l r e s e a r c h Altered GABA neurotransmission in PV-containing neurons impairs prefrontal network synchrony in schizophrenia Reduced GABA signaling from PV-containing GABA neurons to the perisomatic region of pyramidal neurons in the DLPFC might contribute to the pathophysiology of working memory dysfunction via the following mechanisms.76.85 and interactions between ankyrin-G and the cell adhesion molecule. an adaptor molecule that links various membrane proteins to the cytoskeleton. iii) The scaffolding protein gephyrin facilitates the preferential accumulation of gephyrin-GABAA receptor clusters.65 Interestingly.74 enabling them to use this timing mechanism to synchronize the activity of local populations of pyramidal neurons. CCK/CB1R. ii) βIV spectrin.78 and in subjects with schizophrenia. a deficit in the synchronization of pyramidal cell firing.77 Interestingly.

For example. whereas others may be best explained as compensatory responses. No. Lewis DA.93. recent studies indicate that mRNA expression for the α1 subunit of the GABAA receptor in the DLPFC increases across postnatal development. This complex and protracted postnatal maturation of the inputs from PV-containing GABA neurons in the primate DLPFC provides a number of opportunities for even subtle disturbances to have their effects amplified as they alter the trajectories of the developmental events that follow. labor-delivery complications.Lewis Dialogues in Clinical Neuroscience . Lines for each marker represent the percent maximal value achieved plotted against age in months after birth on a log scale. is the neuroplastic capacity of cortical circuitry sufficiently limited that pharmacological augmentation of a compensatory response is feasible? The results of a recent proofof-concept clinical trial suggest that this may be the case. For example. whereas the expression of the α2 subunit declines. For example.94 80 Relative density (%) Neuroplastic responses as targets for treatment The findings reviewed above indicate that working memory and related cognitive impairments in schizophrenia are likely the result of a complex set of alterations in prefrontal excitatory and inhibitory circuitry. raises the possibility that the alterations in schizophrenia of these markers 3m 100 15 m 42 m Ankyrin-G AIS βIV spectrin AIS Gephyrin AIS GABAA α2 AIS GAT1 cartridges PV cartridges Adolescence reflect a disturbance in these patterns of development. whereas the density of gephyrin-labeled AIS is stable through early postnatal development and then then markedly declines during adolescence. Postnatal development of synaptic structure proteins in pyramidal neuron axon initial segments in monkey prefrontal cortex. These temporal correlations may explain how a range of environmental factors (eg. Although speculative. the idea that GABAA receptors contain- 60 40 20 0 . they reflect the morphological and molecular neuroplasticity of DLPFC circuitry in a disease state. Under this scenario. Understanding whether the disease-related change in a given molecule is a consequence or compensation in the disease process has important implications both for the nature of activity of the drugs designed against that target and for the potential therapeutic value of the target. during the perinatal period and adolescence.01 . the elevated α2 subunit expression60 and the decreased α1 mRNA levels92 in schizophrenia might reflect a developmental dysregulation of GABAA receptor α subunit expression.91 Thus. molecular determinants of the structural features that define GABA inputs to pyramidal neuron AIS in monkey PFC undergo distinct developmental trajectories. where the changes in subunit expression with age fail to undergo their full course. 3 . Schematic summary of the trajectories of pyramidal neuron axon initial segments and chandelier neuron axon cartridges labeled with different markers across postnatal development in area 46 of monkey PFC. Lovallo EM. J Comp Neurol. the marked developmental changes in the axon terminals of PV-containing chandelier neurons. 2009. the alterations of DLPFC circuitry in schizophrenia may render it unable to support higher levels of working memory load. PV indicates parvalbumin.Vol 11 . 2009 and βIV spectrin-labeled AIS decline in density during the first 6 months postnatal. Reproduced from ref 90: Cruz DA. Some of these alterations appear to be deleterious causes or consequences of disturbances in the functional architecture of the DLPFC and interconnected brain regions. Stockton S. and the white area indicates the approximate age range corresponding to adolescence in this species. GAT1 indicates GABA membrane transporter 1. Arrowheads demarcate the indicated ages in months. For example. Copyright © Wiley-Liss 2009 277 . urban place of rearing.1 1 10 100 1000 Log age (mo) Figure 4. the current literature raises the possibility that the GABA-related disturbances in schizophrenia represent an arrest of normal developmental trajectories.514:353-367. rendering the impaired performance in schizophrenia analogous to the immature levels of working memory function seen in children.Cortical neuroplasticity in schizophrenia . and their postsynaptic receptors.90 Thus. but then remain stable. with different types of changes occurring during the perinatal period and adolescence (Figure 4). Rasband M. and marijuana use during adolescence) are all associated with increased risk for the appearance of schizophrenia later in life. In each case.

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What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. Neurophysiological correlates of delayed visual differentiation tasks in monkeys: the effects of the site of intracortical blockade of NMDA receptors. Neuroplasticity of neocortical circuits in schizophrenia. 2. perceptual. this type of pharmacological intervention may have particular value as a treatment strategy for highrisk adolescents in the prodromal phase of the illness. Schizophr Res. Mirnics K. En este artículo se revisan las alteraciones en los componentes excitatorios e inhibitorios de los circuitos de la CPFDL desde la perspectiva de la neuroplasticidad del desarrollo y se discuten sus implicancias en la identificación de nuevas terapias. the effectiveness and safety of such interventions requires a fuller understanding of the maturation of these neural circuits. Neurosci Behav Physiol. Farber NB. Bazmi HH. ❏ Acknowledgments: Cited work conducted by the author was supported by NIH grants MH045156. 7. 2003. 2008. Neuroplasticidad de los circuitos corticales excitatorios e inhibitorios en la esquizofrenia La esquizofrenia es un trastorno del neurodesarrollo que se caracteriza por déficit en los procesos cognitivos. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. Disclosure/conflict of interest: David A. Lilly. 2004. Barch DM. Bristol-Myers Squibb. Psychotomimetic. 2003. Krystal JH. Cognitive deficits as treatment targets in schizophrenia. Hashimoto T. los que están mediados por los circuitos de la corteza prefrontal dorsolateral (CPFDL). Gonzalez-Burgos G. Lewis DA. 6. However. NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. 1994. Verma A. 2008. Wu Q.40:881-884. Glutamate receptor dysfunction and schizophrenia. and in 2007-2009 served as a consultant in the areas of target identification and validation and new compound development to AstraZeneca. 2001. 278 . Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression.72:21-28. Moghaddam B.162:475-484. Arch Gen Psychiatry. Estos déficit están asociados con una amplia gama de alteraciones en los circuitos de la CPFDL. Ces déficits s’associent à un ensemble d’altérations des circuits du CPFDL.31:207-218.95 Given the marked developmental changes that occur in each of these systems during adolescence.16:373-379 12. Neuron. Karper LP. Neuroplasticité des circuits corticaux excitateurs et inhibiteurs dans la schizophrénie La schizophrénie est une maladie d’origine neurodéveloppementale caractérisée par un déficit des processus cognitifs transmis par les circuits du cortex dorsolatéral préfrontal (CPFDL). cognitive. 2005.52:998-1007. Lewis currently receives investigator-initiated research support from the BMS Foundation.165:479-489. Lewis DA. J Clin Invest. 10. Am J Psychiatry. 1995. Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis. III. dont certains reflètent la physiopathologie du trouble et dont d’autres sont la conséquence de la neuroplasticité cérébrale en réponse au processus pathologique sous-jacent. Chueva IV. 2009. Am J Psychiatry. Moghaddam B. Hoffman-Roche. 8. 11. Lewis DA. et al.51:199-214. Neuropsychopharmacology Reviews. 3. algunos de ellos reflejan la patología de la enfermedad y otros cómo la neuroplasticidad cerebral responde al proceso patológico subyacente. Green MF. Sheline YI. Cet article propose une revue des troubles des composants excitateurs et inhibiteurs des circuits du CPFDL selon une perspective de neuroplasticité développementale. 1996. MacDonald AW. in humans.Tr a n s l a t i o n a l r e s e a r c h ing α2 subunits are upregulated in pyramidal neurons due to a deficit in GABA input from chandelier neurons led to the use of a novel.33:141-165. Carter CS. Csernansky JG. Sampson AR. Merck. 9. Curridium Ltd and Pfizer. Biol Psychiatry. 4. Snyder AZ. Sweet RA. 1996.

49.80:1149-1158. Lund JS. Abnormally high neuronal density in the schizophrenic cortex: A morphometric analysis of prefrontal area 9 and occipital area 17. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophenia: a possible neurochemical basis for 'hypofrontality'. Melchitzky DS. Arch Gen Psychiatry. 21. Kye CH.12:854-869. 2000.28:239-265. Goldman-Rakic PS. 1995. Functional maturation of excitatory synapses in layer 3 pyramidal neurons during postnatal development of the primate prefrontal cortex. Mirnics K. GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Volk DW. Middleton FA. 2004. et al. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. 2008. 38. Am J Psychiatry.52:258-266. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Auh S. Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study. 58. 52. 53. 39. Rajkowska G. Glantz LA. regional and target specificity of Type I and Type II synapses. Sampson AR. Lewis DA. Sun Z. Uylings HBM. 1982. Pakkenberg B. Proc Natl Acad Sci U S A. Nguyen QL. 40. Hashimoto T.28:599-609. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. NMDA receptors and schizophrenia. Pharmacol Ther. Keshavan MS. 1994. et al. 2005. 23. 2002. 37. In: Peters A. Hyde TM. Goldman-Rakic PS. Vawter MP.387:167-178. Thune JJ. Kim JJ. Volk DW. Neuron. Mol Psychiatry. Austin MC. Pyramidal cell size reduction in schizophrenia: Evidence for involvement of auditory feedforward circuits. 27. Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex. 1999. Middleton FA. Gogtay N. 1999. 2003. 32.46:181189. 279 . 1998.154:1013-1015. 25. Egan MF. 19. Arch Gen Psychiatry. 2001. Potkin SG. Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. 46. Heckers S.54:943-952. Neve RL. Glantz LA. 43. Griffin WST. Sampson AR. Sower AC. Woo T-U. 1975. 1992. Lusk L. J Neurosci. Hashimoto T. Arion D. 20. Arch Gen Psychiatry. Science. Melchitzky DS.7:48-55. J Comp Neurol. 2004. 22. New York. Mol Psychiatry. Biol Psychiatry. Lund RD. of the macaque monkey as shown by retrograde transport of horseradish peroxidase. Am J Psychiatry. Konradi C. 35. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Kristiansen LV. Matus CV. Straub RE.93:14182-14187. Mirnics K. 36. Pierri JN. Cereb Cortex. Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Laminar distribution of cortical efferent cells.35:15-21. Goldman-Rakic PS. 2007. Lewis DA. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Bunt AH. 18. 45. 51. Pettegrew JW. Eggan SM. Nat Neurosci.274:1133-1138. 1997. et al. 2008. Lewis DA.57:237-245.4:78-96. No. Perrone-Bizzozero NI. Jones EG. Neuronal and glial somal size in the prefrontal cortex: A postmortem morphometric study of schizophrenia and Huntington disease. et al. Goldman-Rakic PS. Giedd JN. Synaptogenesis in the prefrontal cortex of rhesus monkeys. Auh S. 1996. J Neurol Neurosurg Psychiatry.Cortical neuroplasticity in schizophrenia . Garey LJ. Lewis DA. Beneyto M. Cerebral Cortex. 2003. 2007. Sampson AR. area 17. The synaptology of parvalbumin-immunoreactive neurons in primate prefrontal cortex. et al. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. 2000. Jones EG. Schizophrenia and the parvalbumincontaining class of cortical local circuit neurons. 1994.28:53-67. J Neurosci.Lewis Dialogues in Clinical Neuroscience .95:5341-5346. Lewis DA. Neuroscience.65:446-453. Levitt P. Mol Psychiatry.103:13214-13219. Shatz CJ. 16. Arch Gen Psychiatry. et al. Lewis DA. Kolluri N. 1996. Leranth C. Akbarian S. Giedd JN. 34. Lewis DA. Rajkowska G. Arellano JI. Ong WY. Sheng JG. Relationship of brainderived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. 47. Benowitz LI. Kroener S. 2001. Reduced pyramidal cell somal volume in auditory association cortex of subjects with schizophrenia. A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. et al. 55. Pucak ML. 2007. 1999. Neuron. 57. Lewis DA. Huttenlocher PR. Dabholkar AS. Am J Psychiatry. The reduced neuropil hypothesis: A circuit based model of schizophrenia. Arch Gen Psychiatry. Lewis DA. Austin MC. 56. Hendrickson AE. 2009 13. 17.158:256-265. Curr Opin Pharmacol. et al. Auta J. Hayes TL. Bourgeois J-P. Volk DW. Pierri JN. Proc Natl Acad Sci U S A.58:11-20. Woo T-U. Arch Neurol.164:287-304. 28.18:626-637. Davis JM. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Bergen SE. 1997. Sun Z. Blumenthal J. 48. et al. Lewis DA. Trends Neurosci. 2005. Spontaneous and evoked synaptic rewiring in the neonatal neocortex.52:805-818. 1995. Anderson S. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Lewis DA.55:215224. Fuchs AF.408:11-22.4:39-45. Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. 2005. 2001. Sweet RA. Magnopyramidal neurons in the anterior motor speech region: Dendritic features and interhemispheric comparisons. Lipska BK. Pierri JN. Chang P. Lewis DA. Huerta I. The origin of efferent pathways from the primary visual cortex. 54. Arch Gen Psychiatry. 1996.55:1128-1137.57:65-73. Neuroscience. Gonzalez-Burgos G. Parvalbumin-immunoreactive axon terminals in macaque monkey and human prefrontal cortex: Laminar. 2000. et al. Pierri JN. 1999. 31. Sampson AR. J Comp Neurol. 14. Sampson AR. Proc Natl Acad Sci U S A. 1998. 33. Proc Natl Acad Sci U S A. Le Be JV. Bird ED. Yuste R. Zaitsev AV. 1997. 50. Williams SM. Lin A.320:353-369.162:1200-1202. Levitt P. Feinberg I. Regional differences in synaptogenesis in human cerebral cortex. Lund JS. Katz LC. Synaptic activity and the construction of cortical circuits. Jeffries NO. 41. NY: Plenum Press. Non-synaptic dendritic spines in neocortex. eds.145:464-469. Lewis DA.45:17-25. Schizophr Res. Selemon LD.58:466-473.24:479-486. 2006. Fairen A. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. Volk CLE.53:1277-1283. Lewis DA. Zuo Y. Selemon LD.13:147-161.67:7-22. J Comp Neurol. Cereb Cortex.17:319-334. Schluterman KO. No deficit in total number of neurons in the prefrontal cortex in schizophrenics. Ivins KJ. Arch Gen Psychiatry. 44. Mrak RE. Markram H. Karson CN. 1984:521-553. Bergen SE. Lewis DA. Crook JM. Unger T. 1995. Pierri JN. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia: regional and diagnostic specificity. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder. 3 . 1997.97:153-179. Woo T-U. 30. Anderson SA. Brain development during childhood and adolescence: a longitudinal MRI study. J Comp Neurol.2:861-863. Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. Neuropsychopharm. Gan WB. Classey JD. Sampson A. Neuroscience. Vol 1. 26. Arch Gen Psychiatry. Marquez A.57:1061-1069. 15. Sweet RA. Sturner WQ. 24. Lewis DA. 2003. Whitehead RE. Synchronous development of pyramidal neuron dendritic spines and parvalbuminimmunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Condé F. 2001. Biol Psychiatry. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. Rakic P. Patel TS. J Psychiatr Res. Espinosa A. Guidotti A. 42. DeFelipe J.Vol 11 . Selemon LD. Sesack SR. Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence? J Psychiatry Res. Meador-Woodruff JH. Dynamic mapping of human cortical development during childhood through early adulthood. 2000. et al. Hashimoto T. 1998. Miller JL.23:6315-6326. J Psychiatry Res. Goldman-Rakic PS.101:8174-8179.25:372-383. 29.

et al. Nusser Z. Gamma oscillations correlate with working memory load in humans. Katona I. 71. Lovallo EM. Bennett V.and cell-type specific firing of hippocampal interneurons in vivo. Lewis DA. J Biol Chem. Rotaru D. Differential synaptic localization of two major γ-aminobutyric acid type A receptor α subunits on hippocampal pyramidal cells. 87. Pouille F. Harvey RJ. 2006. Fritschy J-M. Lambert S. Destruction and creation of spatial tuning by disinhibition: GABAA blockade of prefrontal cortical neurons engaged by working memory.119:257-272. van Leijenhorst L. Eggan SM. Local circuit neurons of developing and mature macaque prefrontal cortex: Golgi and immunocytochemical characteristics.93:11939-11944. Maturation of cognitive processes from late childhood to adulthood. Exp Brain Res. Lewis DA. J Neurophysiol.165:1585-1593. J Comp Neurol. 2007. Lund JS. Lucas MG. Dev Brain Res. Cardin JA. Donohue S. 2005. Chat M. Sieghart W. 65. Hashimoto T. Kubota K. Sampson AR.270:2352-2359.12:1063-1070. Hashimoto T. J Comp Neurol. Trends Neurosci. 76.514:353-367. Ribak CE. Lewis DA. The hierarchical development of monkey visual cortical regions as revealed by the maturation of parvalbuminimmunoreactive neurons. 2009. 2008. Carlen M. Jacobowitz DM. Luna B. Klausberger T. 2007. Scanziani M. Lewis DA. Neurocognitive development of the ability to manipulate information in working memory. Lewis DA. Cruz DA. J Comp Neurol. Parvalbumin is a mobile presynaptic Ca2+ buffer in the calyx of held that accelerates the decay of Ca2+ and short-term facilitation. Matsumura M. Di Cristo G. Fritschy JM. Science.206:397-416. Lewis DA. Rasband M. Delayed response deficits produced by local injection of bicuculline into the dorsolateral prefrontal cortex in Japanese macaque monkeys. Lazar NA.6:312-324. et al. J Neurosci. 2003. Interneuron diversity series: inhibitory interneurons and network oscillations in vitro. et al. 2005. Wu P. 66. 78. Muller M. 60. 1998. Carter CS. 81. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. et al. Celio MR.12:3239-3249. 2008. Cortical inhibitory neurons and schizophrenia.31:257-264. Wieser H-G. Condé F. 2004. 70. Developmental changes in parvalbumin regulate presynaptic Ca2+ signaling. Nature.103:19878-19883. 2004.421:844848. Naiem SS. Yonekawa Y. 2004. Hajos N.341:95-116. Williams GV. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. Rao SG. 73. 280 . Rasband MN. Brain-state.75:1357-1372. Sweeney JA. Marton LF. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. 1993. Reciprocal alterations in pre. Lund JS. Vreugdenhil M. Nguyen QL. Overstreet LS. 2003. Nature. Cereb Cortex. Chandelier neurons in rat visual cortex. 93.89:1414-1422. J Comp Neurol. 2003.and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia.24:7230-7240.459:663-667. Cereb Cortex. 90. 84. Biol Psychiatry. Local circuit neurons immunoreactive for calretinin. Hashimoto T. Fritschy J-M. Schwaller B. A highly sensitive immunofluorescence procedure for analyzing the subcellular distribution of GABAA receptor subunits in the human brain. 2001. Ango F. Lacas-Gervais S. or parvalbumin in monkey prefrontal cortex: Distribution and morphology.176:509-519. Morest DK. Condé F. Protracted developmental trajectories of GABAA receptor alpha 1 and alpha 2 subunit expression in primate prefrontal cortex. Bennett V. 72.Tr a n s l a t i o n a l r e s e a r c h 59. Benke D. Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. 2008. Sawaguchi T. Volk DW. 61. an immunoglobulin family protein. Howard MW. 69. Lewis DA. Traub RD. Aguzzi A. J Neurosci.46:1129-1139. Lewis DA.18:1575-1587. 94. Postnatal development of pre. where do we go? Trends Neurosci. Proc Natl Acad Sci U S A. Gephyrin: where do we stand. Lewis DA. 88. calbindin D-28k. J Cell Biol. 82. Unger T. Eggan SM.96:261-276. Ogawa Y. Proskauer CC. Cereb Cortex. Somogyi P. Collin T. Proc Natl Acad Sci U S A. J Neurosci.17:175-191. 1989. 2007. 1996. Felmy F. Baimbridge KG.26:676-682. J Histochem Cytochem.65:1015-1023. Synapse density regulates independence at unitary inhibitory synapses. Whittington MA. et al. 2000. Caplan JB. Morris HM.293:1159-1163. beta IV spectrin is recruited to axon initial segments and nodes of Ranvier by ankyrinG. Ankyrin G. 2009. 2006. Nat Rev Neurosci. Magill PJ. 63. Ankyrin-based subcellular gradient of neurofascin. Bunge SA. Weinmann O. Lewis DA. 79. Child Devel. 2000. Hashimoto T. Cereb Cortex. Postnatal development of synaptic structure proteins in pyramidal neuron axon initial segments in monkey prefrontal cortex. 1982. 86.65:772-784. Huang ZJ. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. 75. Pierri JN. 2003. Yang Y. Kordeli E. Wendelken C. Arch Gen Psychiatry. Westbrook GL. Jefferys JG. 62. Cholecystokinin innervation of monkey prefrontal cortex: An immunohistochemical study.75:457-469. Solimena M.and post-synaptic GABA markers at chandelier cell inputs to pyramidal neurons in monkey prefrontal cortex. 67. Eggan SM. Lewis DA. 2003. J Neurosci. Lewis DA.20:485-494. Cho RY. 85.27:22612271. 95. 1990. Meletis K. Hedstrom KL. 74. 2003.23:2618-2626. Konecky RO. Cruz DA. 89. Oeth KM. J Comp Neurol. Am J Psychiatry. Fritschy JM.465:385-400. Schneggenburger R. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Cell. Hashimoto T. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Higashiyama H. 2002.25:96-107. et al. 1996. 1995.301:123-137.328:282-312. Crone EA. Peters A. 91. Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Cho RY. Rasband MN. 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along with the expression of a wide array of receptors. Alzheimer’s disease. Magistretti. Using neuroinflammation. astrocyte-neuron interaction. contributing to disease progression. thus compromising neuronal functionality and viability. Magistretti. Brain Mind Institute. Astrocytes are territorial cells: they extend several processes with little overlap between adjacent cells. Switzerland (e-mail: pierre. and defense against oxidative stress. pathogenic stimuli may disturb astrocytic function. including neurotransmitter trafficking and recycling. LLS SAS n the last two decades. transporters. and ion channels. As a result of the growing appreciation of the role of astrocytes in both the normal and diseased brain.dialogues-cns. forming highly organized anatomical domains1-3 which are interconnected into functional syncytia via abundant gap junctions. 2009. we discuss how astrocytic defense mechanisms may be overwhelmed in pathological conditions. Switzerland (Mireille Bélanger). Magistretti) Address for correspondence: Prof Pierre J. these cytoarchitectural and phenotypical features ideally position astrocytes to fulfill a pivotal role in brain homeostasis.12. ideally position them to sense and dynamically modulate neuronal activity. and hepatic encephalopathy as examples.13 Together. as well as various transporters and ion channels. ion homeostasis. hepatic encephalopathy Copyright © 2009 LLS SAS. The critical dependence of neurons upon their constant support confers astrocytes with intrinsic neuroprotective properties which are discussed here. Centre de Neurosciences Psychiatriques. MD. SV 2511 (Bâtiment SV).Tr a n s l a t i o n a l r e s e a r c h The role of astroglia in neuroprotection Mireille Bélanger. intense research efforts aiming to provide a better understanding of astroglial cell function have revealed a number of previously unsuspected roles for these neural cells. brain homeostasis. Conversely.11:281-295.magistretti@epfl. which were long considered as relatively passive structural elements of the brain. EPFL SV BMI LNDC. Switzerland (Pierre J. almost entirely covering their surface. neuroinflammation. Département de Psychiatrie. It has now become quite clear that a plethora of cooperative metabolic processes and interdependencies exist between astrocytes and neurons. CHUV. Ecole Polytechnique Fédérale de Lausanne.5-11 In addition. PhD. © 2009. PhD Astrocytes are the main neural cell type responsible for the maintenance of brain homeostasis. astrocytes project specialized astrocytic endfeet which are in close contact with intraparenchymal blood vessels. 1015 Lausanne. Lausanne. cytokines. They form highly organized anatomical domains that are interconnected into extensive networks. Pierre J. Alzheimer’s disease. energy metabolism. Site de Cery.4 These astrocytic processes closely ensheath synapses and express a wide range of receptors for neurotransmitters. Lausanne.org . Station 19. the traditional neuroncentric conception of the central nervous system (CNS) has been increasingly challenged. and growth factors. All rights reserved 281 www. allowing them not only to sense their surroundings but also to respond to—and consequently Author affiliations: Laboratory of Neuroenergetics and Cellular Dynamics.ch) I Dialogues Clin Neurosci. Keywords: astrocyte. Astrocytes cooperate with neurons on several levels. These features.

white. D-serine.29:32763287.2 In addition. Human astrocytes are more complex then their rodent counterparts. Takano T. 20 µM). A continuously growing body of evidence demonstrates that astrocytes are essential sentinels and dynamic modulators of neuronal function. marks the emergence of an exciting new notion that information processing may not be a unique feature of neurons. for which the term “gliotransmission” has been coined. such as glutamate. Typical human (A) and mouse (B) protoplasmic astrocytes are shown at the same scale for comparison. it is not surprising that alterations in astrocytic function have been shown to have potentially cata- Astrocytes in the normal brain: maintenance of extracellular homeostasis Despite the fact that the brain has a very high metabolic rate. neurons are by nature particularly sensitive to minute changes in their microenvironment. extend 10 times more processes. At the very least. In the present review we discuss the intrinsically protective role of astrocytes in the normal brain. human neocortical astrocytes are 2.65 astrocytes per neuron in the human cortex. Copyright © Society for Neuroscience 2009 282 . In this context.17 Importantly.3. modulate—changes in their microenvironment. the phylogenetic evolution of the brain correlates with a steady increase of the astrocyte-toneuron ratio—going from about 1/6 in nematodes to 1/3 in rodents. 2009. human protoplasmic astrocytes are 2. In this respect.5-fold larger and project 10 times more main processes than mouse astrocytes. or adenosine triphosphate (ATP) which in turn modulate synaptic activity and neuronal excitability (see ref 16 for review). astrocytes play an essential role through a number of cellular processes. the evolutionary pressure exerted on astrocytes highlights the importance of this glial cell type in sustaining normal brain function as the brain itself becomes more complex. Adapted from ref 2: Oberheim NA. Han X. both morphologically and functionally. neuronal function and viability would rapidly be compromised without effective mechanisms for the supply of metabolic substrates and—equally as important— for the removal of waste products. and display unique microanatomical features (Figure 1). Scale bar. (GFAP. it is tempting to hypothesize that the astrocytic contribution to the overall neural network complexity may in part provide the fine tuning necessary to take information processing to a higher level of competence. J Neurosci. This process. Considering the strong metabolic cooperation that exists between these two cell types. and reaching up to 1. contributing to disease progression. and examine how these defense mechanisms may be overwhelmed in pathological conditions. Figure 1. In comparison. Remarkably.Tr a n s l a t i o n a l r e s e a r c h Selected abbreviations and acronyms A AD GSH MCT ROS amyloid-beta Alzheimer’s disease glutathione monocarboxylate transporter reactive oxygen species strophic consequences for neurons. Indeed.5 times larger. more than simply outnumbering their rodent counterparts. such as that seen in humans. astrocytes can respond to neurotransmitters with transient increases in their intracellular Ca2+ levels.15 These Ca2+ signals can trigger the release of neuroactive molecules from astrocytes (or gliotransmitters).2 In light of these evolution-driven modifications. Based on glial fibrillary acidic protein (GFAP) immunostaining. some of the most important are outlined in the following section. they generate more robust intracellular Ca2+ responses to neurotransmitter receptor agonists and display a 4-fold increase in Ca 2+ wave velocity. which can travel through the astrocytic syncytium in a wavelike fashion. Uniquely hominid features of adult human astrocytes. human astrocytes are also strikingly more complex.14. et al.

35 These features. neuronal activity and the resulting propagation of action potentials causes substantial local increases of extracellular potassium ions (K+) in the restricted extracellular space.24 whereas knockout mice for the neuronal EAAC1 display no apparent neurodegeneration. 3 .34 (Figure 2.26 This suggests that modulation of the glutamate uptake capacity of astrocytes may be achievable in vivo with classical pharmacological tools. they increase dramatically during glutamatergic neurotransmission.31 This represents another level of cooperation between astrocytes and neurons. Indeed. its uptake by astrocytes is also crucial in protecting neurons against glutamate-induced excitotoxicity. glutamate is converted to glutamine by the astrocytespecific enzyme glutamine synthetase (GS). in conjunction with the action of the Na+/K+ ATPase.27.19 This concentration of glutamate would cause extensive neuronal injury in the absence of highly efficient mechanisms for its removal at the synapse.27 It is important to note that glutamate can be metabolized in a number of different pathways in astrocytes and neurons.28 Astrocytes are responsible for the replenishment of brain glutamate. orange box). The ammonia produced in the process is thought to be shuttled back to astrocytes following its incorporation into leucine and/or alanine.5-8 These transporters participate in the rapid removal of neurotransmitters released into the synaptic cleft.28 In short.Vol 11 .29 Glutamine is then transferred to neurons in a process most likely involving the amino acid transport systems N.27 Glutamine is then converted back to glutamate via deamination by phosphate-activated glutaminase which is enriched in the neuronal compartment. In the specific case of glutamate. a key enzyme in the main anaplerotic pathway in the brain. γ-aminobutyric acid (GABA).Bélanger and Magistretti Dialogues in Clinical Neuroscience . including oxidation in the tricarboxylic acid (TCA) cycle.20-23 A good example is provided by the phenotypical changes displayed by knockout mice for the various glutamate transporters. Indeed. No.7 A number of in vitro and in vivo studies demonstrate the primary importance of astrocytic glutamate uptake in preventing glutamate-induced excitotoxicity. This is primarily achieved by the astrocyte-specific sodium-dependent high-affinity glutamate transporters GLT-1 and GLAST (corresponding to human EAAT2 and EAAT1. and histamine. Indeed. leading to neuronal hyperexcitability and seriously compromising CNS function.32 Such a scenario is prevented by the buffering of extracellular K+ by glial cells33.Astroglia and neuroprotection . this could dramatically alter the neuronal membrane potential. as they are the only neural cell type expressing pyruvate carboxylase. which is essential for the termination of synaptic transmission and maintenance of neuronal excitability. pink box). 25 Interestingly. Astrocytes also play a central role in the transfer of glutamate back to neurons following its uptake at the synapse. glycine. enable astrocytes to accumulate the excess extracellular K+. suffer lethal spontaneous seizures and selective hippocampal neuronal degeneration. considered the main astrocytic glutamate transporter. resulting in a high membrane permeability to K+.30. L. K+ buffering Apart from the release of neurotransmitters which have to be rapidly removed from the synaptic cleft. knockout mice for GLT-1.34.35 This allows for the spatial dispersion of K+ from areas of high concentration to areas of lower concentration where it can be extruded either 283 . beta-lactam antibiotics have been shown to upregulate the expression of GLT-1 and to prevent neuronal loss both in vitro and in vivo in models involving excitotoxicity. respectively) and to a lesser extent by the neuronal glutamate transporters EAAC1 (human EAAT3) and EAAT4. thus representing a promising therapeutic target for pathologies involving excitotoxicity.36 which can then travel in the astrocytic syncitium through gap junctions down its concentration gradient. 2009 Glutamate uptake and recycling Astrocytic processes surrounding synaptic elements express transporters for a variety of neurotransmitters and neuromodulators including glutamate.18 While basal extracellular glutamate levels are maintained in the low micromolar range. overstimulation of glutamate receptors is highly toxic to neurons (reviewed in detail by Sattler and Tymianski). astrocytes have a strongly negative resting potential and express a number of potassium channels. Without tight regulatory mechanisms. effectively allowing them to synthesize glutamate from glucose. This transfer is achieved by the well-described glutamate-glutamine cycle (Figure 2. Failure to do so would result in the rapid depletion of the glutamate pool in presynaptic neurons and subsequent disruption of excitatory neurotransmission. and ASC in astrocytes and system A in neurons. although glutamate is the primary excitatory neurotransmitter in the brain. reaching up to 1 mM for a few milliseconds in the synaptic cleft.

Abundant carbonic anhydrase (CA) in astrocytes converts CO2 into H+ and HCO3-.are transported into the extracellular space along with one Na+ via the Na+-HCO3. Astrocytic excitatory amino acid transporters (EAATs) are responsible for the uptake of a large fraction of glutamate at the synapse. The resulting CysGly serves as a precursor for neuronal GSH synthesis. Astrocytes release glutathione (GSH) in the extracellular space where it is cleaved by the astrocytic ectoenzyme γ-glutamyl transpeptidase (γGT). Two HCO3.cotransporter (NBC). Astrocytes buffer excess K+ released into the extracellular space as a result of neuronal activity. The lactate produced is shuttled to neurons through monocarboxylate transporters (mainly MCT-1 in astrocytes and MCT-2 in neurons). Potassium ions travel through the astrocytic syncitium down their concentration gradient and are released in sites of lower concentration. where it can be used as an energy substrate after its conversion to pyruvate. The resulting increase in ADP/ATP ratio triggers anaerobic glucose utilization in astrocytes and glucose uptake from the circulation through the glucose transporter GLUT1.Tr a n s l a t i o n a l r e s e a r c h Neurons Astrocytes Capillary CO2 + H2O Na CO2 ATP + Na NHE + H+ NBC HCO3- Na + HCO3H+ CA H+ Pyr H+ MCT2 Lac Gln Glu Lac MCT1 Lac Gln GS K + H EAAT + Glu glu Na+ Lac + GLUT1 Na+/K+ ATPase ADP ATP glucose K+ K+ K + Depolarization K K+ + Glu GSH X CysGly CysGly γGluX γGT GSH GSH Figure 2. 284 . Simplified representation of the main roles of astrocytes in brain homeostasis. Green box: Glutathione metabolism. Pink box: glutamate-glutamine cycle. Protons left in the glial compartment may drive the transport of lactate outside of astrocytes and into neurons through MCTs. Glutamate is converted into glutamine by glutamine synthetase (GS) and shuttled back to neurons for glutamate resynthesis. Yellow box: pH buffering. X represents an acceptor for the γ-glutamyl moiety in the reaction catalyzed by γGT. Excess H+ in neurons is extruded via sodium-hydrogen exchange (NHE). Blue boxes: Lactate shuttle. Orange box: K+ buffering. Glutamate uptake by astrocytes is accompanied by Na+ entry which is counteracted by the action of the Na+/K+ ATPase. thereby increasing the extracellular buffering power.

13 Importantly. 42 Lactate produced by astrocytes as an end result of glycolysis is released into the extracellular space and taken up by neurons via monocarboxylate transporters (MCTs) expressed on astrocytes and neurons.32 Supply of energy substrates Although the brain represents only 2% of the body weight. blue boxes). other mechanisms such as the transient storage of K + ions appear to contribute to the potassium-buffering capacity of astrocytes. white. the morphological features of astrocytes ideally position them to sense neuronal activity at the synapse and respond with the appropriate metabolic supply via their astrocytic endfeet which almost entirely enwrap the intracerebral blood vessels (Figure 3). In addition to spatial buffering. a glucose transporter expressed specifically by glial and capillary endothelial cells in the brain. thus maintaining the overall extracellular K+ concentration within the physiological range.42 Once into neurons. the role of astrocytes in functional hyperemia does not preclude a concerted contribution of neurons via the release of vasoactive substances such as neurotransmitters.Astroglia and neuroprotection . (B) Astrocytic endfeet are in close contact with blood vessels and almost entirely cover their surface (GFAP. Adapted from ref 2: Oberheim NA. In line with this.6diamidino-2-phenylindole . 20 µM). J Neurosci.37 This disproportionate energy need compared with other organs can be largely explained by the energetic cost of maintaining the steep ion gradients necessary for the transmission of action potentials. et al. an increasing body of evidence suggests that astrocytes play a key role in the spatiotemporal coupling between neuronal activity and cerebral blood flow (known as functional hyperemia) in a process that involves transient neurotransmitterinduced increases of [Ca2+]i in astrocytes. Scale bar. and are therefore highly dependent upon a tight regulation of energy substrate supply in order to sustain their normal function and cellular integrity. (A) Protoplasmic astrocytes project specialized processes towards the intraparenchymal vasculature (part of a blood vessel is highlighted in the yellow box) (glial fibrillary acidic protein – (GFAP). lactate can be used as an energy substrate via its conversion to pyruvate by the action of lactate Figure 3.29:32763287. white. it is responsible for the consumption of an estimated 25% of all glucose in the body. Astrocytic endfeet in humans. As mentioned previously.DAPI). 20 µM).40. Copyright © Society for Neuroscience 2009 285 . Scale bar. according to the ANLS. blue. 2009. neurons in particular have very high energy requirements.41 In brief.38 For this reason. and K+ to name a few.Bélanger and Magistretti Dialogues in Clinical Neuroscience . H+. nuclei (4'. 3 . No. nitric oxide. Han X. glutamate uptake into astrocytes following synaptic release causes a stimulation of anaerobic glycolysis and glucose uptake from the circulation via GLUT1. Takano T.Vol 11 .39 Although neurons can import glucose directly from the extracellular space. 2009 into the extracellular space or the circulation. astrocytes have been proposed to play an instrumental role in coupling neuronal activity and brain glucose uptake through a mechanism referred to as the astrocyte–neuron lactate shuttle (ANLS) (Figure 2. the subsequent propagation of Ca2+ waves through the astrocytic syncitium and the release of vasoactive substances (such as arachidonic acid metabolites or ATP) by astrocytic endfeet. Uniquely hominid features of adult human astrocytes.

43 it was recently demonstrated that 2-NBDG (a fluorescent glucose analogue) injected into a single astrocyte in hippocampal slices traffics through the astrocytic network as a function of neuronal activity.55 Beyond lactate. W. 51. in an elegant study by Rouach and colleagues.65 According to this model. glucose delivery into a single astrocyte and its subsequent (and necessary) diffusion through the astrocytic syncitium could rescue neuronal activity.56-58 It has been suggested that this pathway may also serve a neuroprotective purpose by scavenging nonesterified phospholipids which can lead to the production of proapoptotic sphingolipids.by the action of glial CA.52-54 Storage of energy in the form of glycogen is also essential for the preservation of neuronal viability in situations where glucose becomes scarce. glycogen can be rapidly mobilized in response to neuronal activity. Indeed. yellow box). since MCTs exploit proton gradients for the transport of 286 . and released into the extracellular space in the form of lactate which can be used to face the transiently elevated energy requirements associated with neuronal activation. The diffusion of 2-NBGD across the astrocytic syncitium was indeed reduced when spontaneous neuronal activity was inhibited with tetrodotoxin. membrane conductance. pH regulation.43 Interestingly. and energy supply between neurons and glia has been proposed by J. 37.44 posthypoxic recovery. demonstrating that glucose present in the astrocytic network is metabolized to lactate.52 The glycosyl units resulting from glycogen breakdown are fed into the glycolytic pathway of astrocytes. lactate has also been shown to preserve neuronal function in experimental models of excitotoxicity. whereas increasing neuronal activity by means of epileptiform bursts or stimulation of the Schaffer collaterals resulted in the trafficking of 2-NBDG to a larger number of astrocytes. Deiter.45.46 cerebral ischemia.59 pH buffering Another instrumental function of astrocytes in supporting proper neuronal function is their contribution to pH regulation of the brain microenvironment (Figure 2. and used by neurons to sustain their activity.64 although low activity levels are also observed in neurons and in the extracellular space.Tr a n s l a t i o n a l r e s e a r c h dehydrogenase and subsequent oxidation in the mitochondrial TCA cycle.cotransporter (NBC). is their enriched expression of carbonic anhydrase (CA) which converts CO2 into H+ and HCO3-—effectively allowing them to act as a CO2 sink. including energy metabolism. The protons left in the glial compartment could be used to drive the transport of lactate outside of astrocytes through MCT-1 and -4 and its subsequent transport by MCT-2 into neurons. transported out of astrocytes. but that it normally is tightly suppressed. synaptic transmission. it has been demonstrated that brain glycogen levels are increased following mild hypoxic preconditioning in vivo.62 The main feature of glial cells.60-62 Several neuronal processes are strongly affected by relatively small shifts in pH.60.49. CA is preferentially expressed in astrocytes and oligodendrocytes.58.HCO3. For instance.63. it is of interest to note that astrocytes may also transfer other energy substrates to neurons. during periods of high neuronal activity. Indeed.50 In astrocytes.can then be transported into the extracellular space along with one Na + via the Na+.47 and energy deprivation. astrocytes may be able to metabolize fatty acids or leucine to produce ketone bodies which are know to be readily used by neurons as an energy substrate. resulting in significant protection from brain damage as a result of subsequent cerebral hypoxic-ischemic injury. and gap junction communication. suggesting that intracellular glycogen is actually toxic to neurons.50 Failure to do so results in neuronal apoptosis. it has recently been demonstrated that neurons also possess the enzymatic machinery to synthesize glycogen. The existence of a lactate shuttle between astrocytes and neurons is supported by a number of experimental studies (reviewed in ref 41). endowing them with a high pH buffering capacity. the CO2 produced by elevated (mostly neuronal) oxidative metabolism diffuses into glial cells and is converted to H+ and HCO3. thereby increasing the extracellular buffering power.62 A coupling mechanism which integrates synaptic transmission.61.49 Interestingly. Two HCO3. This effect was mimicked by lactate but was abolished in the presence of the MCT inhibitor αcyano-4-hydroxycinnamic acid (4-CIN). in the CNS glycogen is almost exclusively present in astrocytes and virtually constitutes the only energy reserve. For example.43 They next went on to show that during glucose deprivation which resulted in a 50% depression of synaptic transmission in hippocampal slices.48 highlighting the importance of astrocyte-derived lactate for neuronal function and viability. evidence suggests that in certain conditions. neuronal excitability. Indeed. Another key feature of astrocytes is their capacity to store glucose in the form of glycogen.

via the Na+. and thus fulfills its antioxidant role either by directly reacting with ROS or by acting as a substrate for glutathione S-transferase or glutathione peroxidase. and catalase).74 or iron. thereby alleviating the metabolic burden on the glial Na+/K+ ATPase. Accordingly. Both neurons and astrocytes can synthesize the GSH tripeptide (L-glutamyl-Lcysteinylglycine) by the sequential action of glutamate cysteine ligase and glutathione synthetase. ascorbate. 3 .Vol 11 . according to the ANLS hypothesis.72. cannot use the cysteine-oxidation product cystine as a precursor. dehydroascorbic acid.74 This neuroprotective capacity of astrocytes may derive from the fact that they possess significantly higher levels of a variety of antioxidant molecules (including glutathione. glutathione peroxidase. neurons are highly dependent on astrocytes for their own GSH synthesis.67 Compared with neurons. 69. astrocytes display a much more effective artillery against ROS. However. protons released into the extracellular space may also be reconverted to CO2 and water by the action of extracellular CA at the expense of one HCO3-.40. and is also an important cofactor for the recycling of oxidized vitamin E and GSH. which are involved in metal binding and iron trafficking.Astroglia and neuroprotection .65 Defense against oxidative stress Oxidative stress occurs as a result of an imbalance between the production of reactive oxygen species (ROS) and antioxidant processes.69.83 This shuttling of GSH between astrocytes and neurons is essential in providing precursors for neuronal GSH synthesis (Figure 2. and vitamin E) and display greater activities for ROS-detoxifying enzymes (including glutathione S-transferase.61 This model suggests that pH buffering taking place in glial cells during neuronal activation may also act cooperatively to: i) contribute. unlike astrocytes. it appears that astrocytes may also play an active role in preventing the generation of free radicals by redox active metals. respectively. to the extrusion against its concentration gradient of the excess intracellular Na+ resulting from glutamate uptake in astrocytes. 85.68 Astrocytes are responsible for the uptake of the oxidation product of ascorbate. Ascorbate can directly scavenge ROS. including neurodegenerative diseases.cotransporter.61.70 hydrogen peroxide. which can then be taken up by neurons directly or after undergoing further cleavage by extracellular neuronal aminopeptidase N to form glycine and cysteine. and ii) drive the efflux of lactate which is produced in response to glutamate uptake in astrocytes.41 Alternatively. the rate-limiting substrate for GSH synthesis. The latter can then either be used intracellularly in astrocytes. this lactate can then be used as an energy substrate by neurons. combined with a relatively low intrinsic antioxidant capacity. thus providing an energy substrate for the neuronal TCA cycle. or released into the extracellular space to be utilized by neurons for their own antioxidant defense. as illustrated by the fact that GSH levels are higher in neurons when they are cultured in the presence of astrocytes. No.83 This thiol compound can act as an electron donor. and stroke.71-73 superoxide anion combined with nitric oxide. as they participate in metal sequestration in the brain.84 Astrocytes release GSH in the extracellular space.68 287 . neurons show increased resistance to toxic doses of nitric oxide.HCO3.68. from the extracellular space and its recycling back to ascorbic acid.68 This is supported by a number of studies demonstrating that when cultured in the presence of astrocytes. traumatic brain injury.66 suggesting that the CNS is particularly vulnerable to oxidative injury. increasing the capacity to synthesize GSH specifically in astrocytes by increasing their capacity to uptake cystine significantly enhances the neuroprotective effect of astrocytes against oxidative stress.87 The recycling of ascorbate is another example of cooperation between astrocytes and neurons for antioxidant defense. 2009 lactate. where it is cleaved by the astrocytic ectoenzyme γ-glutamyl transpeptidase (γGT) to produce CysGly. green box).79 This is achieved in part through their high expression levels of metallothioneins and ceruloplasmin.41. It is known to be involved in a number of neuropathological conditions.75-78 In addition.Bélanger and Magistretti Dialogues in Clinical Neuroscience .86 Conversely.83 The importance of this cooperative process for neuronal defense against oxidative stress is evidenced by the reduced ability of GSHdepleted astrocytes to protect neurons against oxidative injury. cooperative astrocyte-neuron defense mechanisms against oxidative stress seem to be essential for neuronal viability. This can be explained by the brain’s high rate of oxidative energy metabolism (which inevitably generates ROS).61 As previously discussed. since neurons.80-82 Glutathione (GSH) is the most important antioxidant molecule found in the brain.69. This is especially true for cysteine.

Tr a n s l a t i o n a l r e s e a r c h Astrocytes in the diseased brain: a fine balance Considering the extensive functional cooperativity that exists between neurons and astrocytes. IL6. In this regard. Neuroinflammation The brain can mount an immune response as a result of various insults such as infection. for instance. the insult may persist and/or the inflammatory process may get out of control. This may reflect a common underlying phenomenon by which disease progression is associated with chronic and/or escalating harmful stimuli that eventually exhaust the neuroprotective mechanisms of astrocytes. The most likely answer is that it is neither exclusively one nor the other. it constitutes a beneficial process aiming to protect the brain from potentially deleterious threats. astrocytes can become activated— a process known as astrogliosis. hypertrophy. and fibroblast growth factor (FGF)-2. deleterious pathways may then be turned on in astrocytes. multiple sclerosis. it is important to note that astrocytes are immunocompetent cells as well. Instead. metabolic failure. and that they act as important regulators of brain inflammation. astrocytes express several cytokine receptors and can therefore also be a target of cytokine signaling through autocrine or paracrine mechanisms. excitotoxicity. and proliferation. Like microglia.11 While cytokines are categorized as proinflammatory or anti-inflammatory. Neuroinflammation has indeed been implicated in several neuropathologies including Alzheimer’s disease. In most cases. IL-15.93 Additionally. Even worse. cytokines can potentially mediate both neuroprotective and neurotoxic processes at once. namely neuroinflammation. that may exert either neuroprotective or neurotoxic effects.and anti-inflammatory—as well as neurotoxic and neurotrophic—processes. Alzheimer’s disease.or anti-inflammatory). For example. are major effectors in this fine balance as they exert a dual role. chemokines.92 Activated astrocytes can release a wide array of immune mediators such as cytokines. directly contributing to the pathogenic process.102 and neurotrophic factor production.101 ischemic tolerance. injury. or abnormal protein aggregates. and growth factors. Interestingly. ciliary neurotrophic factor (CNTF). several neurological diseases share common pathogenic processes.11. astrocytes can themselves respond to IL-1β by releasing a number of potentially neuroprotective trophic factors such as nerve growth factor (NGF). amyotrophic lateral sclerosis. TNFα.91 While microglial cells are generally considered the main resident immune cells of the brain. A role of astrocytes has been described in a number of brain pathologies. or inflammation—many of which are known to be counteracted by the function of astrocytes in the normal brain (see previous sections). cellular debris. IL-10. which is characterized by altered gene expression. and TGFβ). ample evidence indicates that IL-1β may exacerbate neuronal injury both in vivo and in vitro.100 blood-brain barrier repair. Parkinson’s disease. potentially sustaining or suppressing neuroinflammation (hence their traditional labeling as pro. as many of them interact with each other (either antagonistically or synergistically) and may additionally have pleiotropic effects. glial cell-line derived neurotrophic factor GDNF. and stroke.96-99 In contrast. and may negatively affect neuronal function and viability. In some situations. and that the overall consequences of an immune activation of astrocytes is the result of a complex interplay between pro. dissecting out the exact neuroprotective and neurotoxic contributions of astrocytes in neuroinflammatory processes has proven to be extremely challenging because they are capable of releasing such an extensive repertoire of cytokines in response to various stimuli (some examples include interleukin (IL)-1β.103-106 Importantly. one can expect that alterations of astrocytic pathways in response to pathological stimuli will result in (or at least contribute to) neuronal dysfunction.93 Adding another level of complexity. understanding their exact individual effect is far more complex.107-109 Taken together. Chronic neuroinflammation sets in as a result. and hepatic encephalopathy.95 As a result.11. studies such as those mentioned above provide important information about the multiple 288 .94 This has led to considerable debate as to whether activation of astrocytes is beneficial or detrimental to neighbouring neurons. we focus on three pathological processes that well illustrate the dual role of astrocytes in neuroprotection and neurotoxicity. activated astrocytes can release potentially deleterious ROS and form a glial scar which may impede axon regeneration and neurite outgrowth. however. IL-1β has also been implicated in neuroprotective processes such as remyelination. such as oxidative stress. and a complete review is beyond the scope of this article (see refs 88-90). Cytokines. thus contributing to disease progression. INFβ.

129 Similarly in ex vivo studies. 3 . it is interesting to note that astrocytes appear to participate in the suppression of microglial activation through negative feedback loops. Reactive astrocytes.118-120 To summarize. and by disturbances in behavior and personality.127.131 Interestingly. and preserving neuronal viability. glial cell activation and astrocytic accumulation of Aβ can be observed even preceding plaque formation. is characterized by the progressive decline of cognitive functions including memory and mental processing. like microglia. astrocytes surrounding plaques in autopsy material from the brain of AD patients contain intracellular Aβ deposits. 122 Alois Alzheimer himself in 1910 suggested that glial cells may participate in the pathogenesis of dementia123. affords substantial neuroprotection following spinal cord injury. Sofroniew and colleagues have demonstrated that following various types of brain injury. a central role of Aβ peptides in concert with neuroinflammation is generally accepted. No. Several observations support an active role of astrocytes in Aβ clearance. However. internalization. when exogenous astrocytes were transplanted into the brain of Aβ plaque-bearing transgenic mice. For instance. has provided important new insight into their overall role in response to brain injury.110 By contrast. thus avoiding the accumulation of toxic extracellular Aβ. using a transgenic mouse model in which dividing reactive astrocytes were selectively ablated. Activated microglial cells release high levels of proinflammatory cytokines and toxic ROS which may negatively impact neuronal survival. Though the exact pathophysiological mechanisms leading to synaptic loss and the resulting cognitive decline have not been fully elucidated. 289 .121 Typical histopathological features of the AD brain are amyloid-β (Aβ) plaques which may contain dystrophic neurites. and reactive gliosis. the complex interplay between the various cytokines released by astrocytes and surrounding cells.129 The physiological importance of Aβ clearance by glial cells in vivo is evidenced by the increased Aβ accumulation and premature death observed in a transgenic mouse model of AD when microglial activation was impaired. as well as in promoting blood-brain barrier repair. they migrated towards Aβ deposits and internalized Aβpositive material. As such.114 Several in vitro studies have demonstrated that astrocyte-conditioned medium or the presence of astrocytes attenuates microglial activation in response to various proinflammatory stimuli. it has been demonstrated that the selective attenuation of astrocytic proinflammatory processes. For this reason.128.124.111-113 Consistent with a role of astrocytes in containing neuroinflammation. they may only reflect a small fraction of an infinitely more intricate process in which astrocytes take part. as available evidence can argue both for neuroprotective or neurotoxic effects.132 suggesting that astrocyte cells attempt to scavenge Aβ early in the progression of the disease. vascular amyloidosis.128.115-117 The exact nature of the astrocyte-derived factors involved has not been fully elucidated. 2009 effects of individual cytokines. which likely reflects an effort to limit its extracellular deposition. it must be emphasized that the overall effect is dependent on the fine balance between a number of factors including the type.115 This may in part explain the neuroprotective effect of TGFβ in experimental models of excitotoxicity or ischemia. they also have major limitations.and anti-inflammatory pathways at a time.Vol 11 . if inflammatory activation of astrocytes unquestionably has consequences for neuronal function and viability. through genetic inactivation of the transcription factor NF-κB specifically in this cell type.Astroglia and neuroprotection . duration.125 and both cell types have been shown to be capable of internalizing and degrading Aβ peptides. reactive astrocytes play an essential role in temporally and spatially restricting neuroinflammation. neuronal and synaptic loss. limiting brain edema. their exact role is still a matter of debate. the use of genetically manipulated animal models specifically preventing the proliferation of reactive astrocytes or the activation of their core inflammatory pathways.126-129 This is thought to be a neuroprotective mechanism by contributing to the clearance of Aβ from the extracellular space. and degradation of Aβ could be observed when cultured astrocytes were seeded on top of plaque-bearing sections prepared either from the brains of AD patients or transgenic mice models of AD. the most prevalent neurodegenerative disorder. are observed in close association with Aβ plaques in the brains of AD patients.Bélanger and Magistretti Dialogues in Clinical Neuroscience . intracellular neurofibrillary tangles. Alzheimer’s disease Alzheimer’s disease (AD). For example. however.94. and the receptors for cytokines and growth factors expressed by these neighboring cells. and severity of the insult. in that they can only take into account a few pro. but transforming growth factor (TFG)β is thought to contribute to this process. binding.130 In addition.

astrocytes may provide significant protection through the negative regulation of microglial reactivity following exposure to Aβ. In its acute form.154-156 Conversely. Hepatic encephalopathy Hepatic encephalopathy (HE). a hallmark of AD.150 This enhancement of the basal inflammatory state. For example.Tr a n s l a t i o n a l r e s e a r c h Although their contribution to the clearance of Aβ deposits is thought to be protective. thus perpetuating glial cell activation. astrocytes and microglia can release a number of inflammatory mediators which may be toxic for surrounding neurons. it relies 290 . in the presence of microglia.154-156 In mixed cultures. suggesting that Aβ interacts directly with the astrocytic network. For instance. microglial phagocytosis was shown to be markedly suppressed in the presence of astrocytes. This may in part explain why age is the most important risk factor for developing AD since increased neuroinflammation is associated with normal aging. the overwhelming combined effect of Aβ accumulation. sometimes propagating as intracellular calcium waves.152 Besides proinflammatory cytokines.132. which occurs as a result of cytotoxic swelling of astrocytes.144-146 Moreover. intracellular Ca2+ signaling was reported to be abnormally increased in astrocytes. together with the gradual accumulation of Aβ which is also seen in the normal aging brain. which resulted in increased persistence of senile plaques when presented to microglia in vitro. One obvious explanation is that the physiological functions of astrocytes may be directly affected by Aβ.139-143 Proinflammatory cytokines have been shown to exacerbate the microglial response to Aβ and to enhance its neurotoxic effects.142. and reactive oxygen and nitrogen species (RN/ROS) such as NO and O2-.159 Although HE is a multifactorial disorder. neuroinflammation.133 The involvement of glial cells in the pathogenesis of AD is supported by several in vitro studies demonstrating that their interaction with Aβ impairs neuronal viability or worsens the neurotoxic effect of Aβ. a neuropsychiatric syndrome occurring as a result of chronic or acute liver failure. it appears that proinflammatory cytokines can also increase the expression of the amyloid precursor protein and its processing through amyloidogenic pathways. In line with this. which in turn promotes the synthesis and accumulation of more Aβ. is one of the first identified neurological disorders involving astroglial dysfunction as its primary cause. resulting in neuronal cell death. This is supported by studies testing newly identified antiinflammatory molecules which selectively suppress proinflammatory cytokines production in glia. the symptoms of HE can progress rapidly from altered mental status to stupor and coma.137.133 These Ca2+ transients were only observed after the mice developed senile plaques and were uncoupled from neuronal activity.153 Astrocytes have been proposed to take part in this process. As the disease progresses. RN/ROS produced by activated astrocytes and microglia may contribute to disease progression by inducing oxidative stress. this must be interpreted with caution since. and oxidative stress may tip the scales away from the neuroprotective functions of astrocytes and towards the activation of deleterious pathways. The most important cause of mortality in acute liver failure is brain herniation. glial cells may provide a valuable therapeutic target for the treatment of AD.157 However. in a elegant study using fluorescence imaging microscopy in live mice bearing AD-like pathology.159 Ammonia rapidly accumulates in the blood as a result of acute liver failure and can readily cross the blood-brain barrier. may provide the trigger necessary for this vicious circle to set in. resulting in a significant attenuation of synaptic dysfunction and neurodegeneration and in behavioral improvements in experimental models of AD. Examples include proinflammatory cytokines such as IL-1β and IL-6.151. there is also evidence to suggest that microglia and astrocytes contribute to the progression of AD. Because of their central role in neuroinflammation (see previous section). Because the brain does not possess an effective urea cycle.158 In summary. these effects were accompanied by decreases in GSH levels in both astrocytes and neurons. and may cause death within days. as previously discussed.134-138 Upon their activation by Aβ. ammonia is thought to play a central role in its pathogenesis.147-149 Aβ accumulation may therefore establish a vicious circle whereby neuronal stress and glial activation initiates an inflammatory response. the apparently conflicting roles of astrocytes in the progression of AD may be explained by the coexistence of potentially protective and deleterious pathways in activated astrocytes. Aβ causes intracellular Ca2+ transients and stimulates the production of ROS by NADPH oxidase in astrocytes but not in neurons. increased microglial phagocytosis associated with their activated state may be neuroprotective. leading to intracranial hypertension.

Bonvento G. Brain Res Brain Res Rev. this protective mechanism is exhausted and astrocytes swell as a result. Glial transporters for glutamate. 2000. Fischer H.9:10-22. Gadea A.64:218-222. Trends Mol Med. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Glial cells participate in histamine inactivation in vivo. Tran MH. 14. Neurons set the tone of gap junctional communication in astrocytic networks. Lopez-Colome AM.103:13606-13611. Astrocytic neurotransmitter receptors in situ and in vivo.29 Ammonia detoxification is an essential homeostatic function of astrocytes. Steinhauser C. understanding astrocytic function is key to providing a better grasp of brain function in general and how it may go awry. Nedergaard M.162 Such a mechanism may contribute to trap glutamine in astrocytes and promote swelling. 2007. No. 8. Takano T. Danbolt NC. 3100AO-108336/1 to PJM). Halassa MM. Conclusion Astrocytes are known to be the most important neural cell type for the maintenance of brain homeostasis. Rouach N. as they should take into account the multiple interactions and interdependencies between neural cell types. and GABA III. Haydon PG. together with an impaired capacity of astrocytes to fulfill their role in ammonia detoxification. Xu Q. Glial regulation of the cerebral microvasculature. Philippu A. 1990. Trends Neurosci.Bélanger and Magistretti Dialogues in Clinical Neuroscience . This is thought to be accomplished by the release of osmolytes such as taurine and myo-inositol by astrocytes in response to glutamine accumulation. Wang X. Prog Neurobiol. and GABA: II.32:380-412. glycine. Brosnan CF. the astrocytic accumulation of osmotically active glutamine as a result of ammonia detoxification is thought to contribute at least in part to the swelling of astrocytes in hyperammonemic conditions. 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Interferon-gamma increases neuronal death in response to amyloid-beta1-42. Hirsch E. J Physiol Paris. Angeretti N. Craft JM. Dal P. 2001. Paradisi S. Bianca VD.24:565-575. et al. Silver J.46:252-260. Cohen M. Eikelenboom P. Brain Res Mol Brain Res. Brusilow SW. von Bernhardi R. 156. Evidence of oxidative stress in Alzheimer's disease brain and antioxidant therapy: lights and shadows.323:1211-1215. Exp Neurol. van Beelen AJ. Norenberg MD. Bianchini E. Abramov AY. Frautschy SA.95:57955800.261:H825-H829. Ajmone-Cat MA. J Neuroinflammation. The presence of astrocytes enhances beta amyloid-induced neurotoxicity in hippocampal cell cultures. Kuchibhotla KV. Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation. 2008. Watterson DM. Frenkel D. 148. Panickar KS. 2002. 2005. Sheng JG. A possible inflammatory mechanism of neuronal damage in Alzheimer's disease. Rossi F.

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Biology (Phyllis M. and on the age and health status of the women who receive hormone therapy. USA (E-mail: pmwise@u. 2009. immune system. Wise). We realize more than ever that the effects of estrogens (with and without simultaneous or sequential progestins) are diverse and sometimes opposite. animal model Author affiliations: Departments of Physiology and Biophysics (Phyllis M. University of Washington. Wise. but can also stimulate the birth of new neurons. All rights reserved Address for correspondence: Dr Phyllis M. depending on the use of different estrogenic and progestinic compounds.11:297-303. Candice M. Women usually undergo the menopausal transition when they are about 51 years of age.Tr a n s l a t i o n a l r e s e a r c h Estradiol: a hormone with diverse and contradictory neuroprotective actions Phyllis M. Clearly. on treatment sequence. many factors.org . the dose and route of administration.dialogues-cns. Seattle. Candice M. on different delivery routes. brain injury. neuroprotection. estrogen therapy. We hope that this update will encourage even richer dialogues between basic and clinical scientists to ensure that future clinical studies fully consider the information that can be derived from basic science studies. and the age and previous hormonal and health status of the women being treated. Shotaro Suzuki. Shotaro Suzuki. on different concentrations. Here we posit the concept that estrogen’s modulation of the immune status may be the basic mechanism that underlies its ability to protect against neurodegeneration and its powerful neuroregenerative actions. PhD. WA 98195-1237. we have learned that estrogens cannot only protect against cell death. PhD n 2002 we contributed an article to Dialogues in Clinical Neuroscience which discussed the neuroprotective actions of estrogens. must be taken into consideration when designing clinical studies and when interpreting results. In addition. Box 351237. © 2009. USA Copyright © 2009 LLS SAS. Wise. Brown). neurogenesis. and will discuss the importance of the accumulating data that point to the complexities of estrogen action. we have gained an increasing appreciation of the impact of estrogens on the immune system and on inflammation. LLS SAS I Dialogues Clin Neurosci. which may be abrupt or may occur over a period The concept that estrogens exert important neuroprotective actions has gained considerable attention during the past decade. menopause. Seattle. stroke. Wise). This dramatic physiological change. inflammation. and Obstetrics and Gynecology (Phyllis M. Wise. Brown. Keywords: estradiol. including the type of estrogen used. PhD.1 In this review we build on the understanding we had at that point. cell death. Only then will we have a better understanding of the impact of hormones on the menopausal and postmenopausal period in a woman’s life. Numerous studies have provided a deep understanding of the seemingly contradictory actions of estrogens.edu) 297 www. Washington.washington. 301 Gerberding Hall. During the past few years.University of Washington.

the brain (neurons. and not hemorrhagic. and the hippocampus. affects 500 000 Americans each year. a greater number of women and a larger proportion of women are destined to spend over three decades of their lives in a hypoestrogenic state. cerebrovascular stroke. This makes it imperative that we understand the intricacies of estrogen action. while the age of menopause has remained fixed at age 51. this interpretation has been questioned since recent clinical trials including the Women's Health initiative (WHI) reported negative impact of estrogen therapy (ET)4. The postmenopausal period is often associated with vaginal dryness.Tr a n s l a t i o n a l r e s e a r c h of a few years.6-8 and some studies in animal models also suggest that estrogens are not universally protective and can be deleterious under some circumstances. Thus. Since most cerebrovascular strokes (>70%) in aging human populations are ischemic. the ischemic penumbra. the actions of these different compounds are diverse. Blockade of this artery at its base results in about a 50% decrease in blood flow and causes severe metabolic impairment in a core region. When used in hormone therapy for postmenopausal women. Over the past century the average life expectancy in the United States has increased to over 80 years.4 Initially. are thought to produce it as well. is marked by a decline in ovarian hormone secretion and cessation of reproductive fertility. and bone. their related compounds. this gender difference was thought to be explained by a combination of both the longer life expectancy of women and the protective roles of estrogen. since the incidence of stroke increases after menopause and the risk continues to rise with age. and a panel of neurological manifestations such as hot flushes. 5 However. we adopted an animal model that reproduces ischemic infarcts. Thus. and Alzheimer's disease. regions that surround the ischemic core. is an 18 carbon (C-18) steroid with an aromatic A-ring. undergo more moderate metabolic impairment and are potentially salvageable by effective therapeutic agents. but is also a precursor to estrogens. when it is protective. and greater instances of sleep disturbance. and microglia).9 In an attempt to reconcile these seemingly contradictory data. a wide variety of estrogenic and progestogenic compounds are synthesized in other species or are pharmacologically manufactured through pathways that have been developed by researchers and have been used widely by the pharmaceutical industry. Estrogens and stroke: use of animal models to decipher mechanisms of action Even the best. urinary symptoms. cells of the immune system. which vascularizes the cerebral cortex. since studies performed with experimental animal models allow replication with adequate numbers of animals. whether they are given simultaneously or sequentially. including adipose tissue. other organs and tissues. We have previously demonstrated that E2 Estrogens and stroke Stroke is the third leading cause of death for middleaged and older women and a major health problem that 298 . investigators have developed several animal models to investigate the pathophysiology and potential treatments for stroke. Estradiol-17β (E2). It is synthesized mainly by the ovary. our lab has used animal models to explore the mechanisms of estrogen’s neuroprotective and neuroregenerative actions. the striatum.3 Every year approximately 40 000 more women than men are affected by stroke. Turgeon et al2 have provided a detailed review of our current understanding of estrogens. and lack of selection or recall bias. today. osteoporosis. wellcontrolled environments during the entire study. and antagonists. Their effects depend upon the concentration. to examine the effects of estrogen in neurodegeneration. more than ever before. emotional instability. and on the age and health status of the women who receive hormone therapy. the route of delivery. progestogens. We have utilized permanent middle cerebral artery occlusion (MCAO) as a model of permanent occlusion of the middle cerebral artery. however. which is not only an active hormone in and of itself. agonists. controls with equivalent genetic backgrounds and previous exposure to similar environments. and when it increases risk. astrocytes. complex. Progesterone is a C-21 steroid hormone. the predominant and most biologically active estrogen. Estrogens and progestins Estradiol and progesterone belong to a family of steroid hormones with complex actions. called the “ischemic core” and many neurons in these regions die by necrosis within hours following injury. In addition to the estrogens and progestins produced in human tissues. well-designed clinical studies cannot benefit from the experimental advantages of many basic science studies. and sometimes contradictory. In contrast.

10-12 Studies in the early 1990s suggested that estradiol is a neuroprotective factor that profoundly attenuates the degree of ischemic brain injury: i) female gerbils demonstrate less neuronal pathology than males after ischemia induced by unilateral carotid artery occlusion. These components of inflammation may interact with each other and are not mutually exclusive. concentrated levels of nitric oxide that promote neuronal cell death. exert profound neuroprotective actions after MCAO. ii) activation of the enzyme.25 Estrogen receptor α mediates estrogen’s neuroprotective actions To date.14 Further. and astrocytes are the primary source of the iNOS enzyme during stroke. and this response is also regulated by both estrogen receptors.Estrogen and stroke injury . No.16 Consequently. E2 suppresses microglial activation. we found that the presence of this receptor subtype is a prerequisite for 299 . the ability of E2 to exert protective action against ischemic injury. and cerebrovascular stroke include inflammation processes in the underlying mechanisms of the disorder.10-13 We have also demonstrated that E2 effectively reduces the infarct volume in middle-aged animals. These studies demonstrate that estrogens act not only on neurons and astrocytes. and Alzheimer’s disease.18 Using ERα knockout mice. migrate to the site of injury. multiple sclerosis.19 In vivo and in vitro models of brain injury and neurodegenerative diseases have provided substantial evidence that physiological levels of E2 suppress inflammation through ERα and ERβ (reviewed in refs 19-22). We have shown that low. iii) both ovariectomized females and castrated males that are treated with estradiol suffer less MCAO-induced injury than vehicle-treated gonadecetomized controls. proliferate. Microglia become activated in response to injury. and immune systems to fully appreciate the protective role of E2 during neurological diseases and injury. but also on microglia. inducible nitric oxide synthase (iNOS). Since the discovery of the second form of ER (ERβ) in 1996. Parkinson’s disease. Many neurological disorders such as Alzheimer’s disease.17. Recently. suggesting that a constellation of factors responsible for mediating E2’s protective actions is preserved during the initial stages of aging. we have found that E2 must be administered prior to the onset of injury. stroke.18 Taken together. Activation of iNOS during stroke produces high. ii) female rats sustain over 50% less infarction than males and ovariectomized female rats following ischemia induced by transient occlusion of the middle cerebral artery (MCA).19.Wise et al Dialogues in Clinical Neuroscience . compared with their hypoestrogenic counterparts. but an accumulating body of evidence clearly shows that estrogens may directly or indirectly regulate three components of the inflammatory response: i) microglial activation. peripheral infiltrating macrophages. and change in both morphology and cell surface markers.15 Collectively. two forms of nuclear estrogen receptor (ER) have been cloned. we found that ischemic injury upregulates ERα expression in the cortex of ovariectomized animals without influencing ERβ expression. Many studies have shown that E2 suppresses iNOS in animal models of neuroinflammation.19. researchers have investigated the similarities and differences in the distribution and actions of these two forms of ER. we must be careful in extrapolating from rodents to humans until the appropriate clinical studies are performed. 3 . endocrine. the injured brain seems to provide signals conveying the need for the reappearance of ERα. since acute administration of E2 at the time of injury does not reduce the extent of infarction.Vol 11 .23 The inflammatory response associated with stroke is complex. the resident macrophages of the brain (Figure 1). Anti-inflammatory actions of estrogens More recently we have begun to appreciate the importance of inflammation in neurodegeneration and the role of E2 acting as an anti-inflammatory factor. and iii) the activation of cytokines/chemokines. physiological levels of E2. Microglia.24.1 Our work has contributed significantly to the understanding of the neuroprotective actions of physiological levels of E2. which may mediate the ability of E2 to protect against neuronal apoptosis and possibly reinitiate differentiation of the injured brain. 2009 exerts powerful neuroprotective action in ischemic penumbra where E2 protects neurons from delayed programmed cell death or apoptosis. and this response is regulated by both estrogen receptors. we hypothesized that the dramatic re-expression of ERα after stroke injury mediates E2’s profound neuroprotection against ischemia. However. These studies also highlight the tremendous importance of understanding the crosstalk between the nervous. the results of these studies suggest that postmenopausal women who are estrogenreplaced may suffer a decreased degree of brain injury following a stroke.

both ERα and ERβ play essential functional roles. whether they migrate to the site of injury. and maturation of neurons.27 Studies from our laboratory have shown that immediate treatment with E2 following MCAO suppresses brain levels of the proinflammatory cytokines IL-6 and MCP1. Importance of timing of estrogen therapy Recent studies describing the seemingly contradictory actions of estrogens in stroke injury have led us to believe that the timing of estrogen therapy relative to the time of the menopause may be an important factor to consider. There is a positive correlation between high levels of proinflammatory cytokines in serum or cerebrospinal fluid greater stroke severity.Tr a n s l a t i o n a l r e s e a r c h Cytokines are secreted proteins that appear to play a critical role in the pathophysiology of human cerebral ischemia.27 In several different brain injury paradigms. and thus. Although precise roles for each ER form are yet to be determined. and the presence of both receptor forms is the prerequisite for E2 to enhance neurogenesis. Estradiol influences neurons. The ability of estrogens to exert trophic and protective actions depends upon their ability to alter the birth and death of neurons. but also can be produced by neurons. survival. tumor necrosis factor alpha (TNF-α). the mean age of the subjects was 63 years. pro. and factors which influence.16. We have explored whether E2 stimulates generation of newborn neurons after stroke. astrocytes. and microglia through altering the expression of a broad profile of neurotransmitters and neuropeptides and their receptors. our study clearly demonstrates that the presence of both receptors is important in expansion of neuronal populations in the subventricular zone after ischemic injury.16 Estradiol and neurogenesis One of the most remarkable discoveries in modern neuroscience is that the adult brain continues to generate new neurons under both normal and neurodegenerative conditions. we have not been able to determine whether these newborn neurons actually differentiate into mature neurons at this time point. physiological levels of E2 increase the number of newborn neurons (Figure 2). and enhances the production anti-inflammatory cytokines.and anti-inflammatory agents. It is important to remember that in the WHI. Figure 2. Estradiol influences the number of newborn neurons. the majority of subjects were 12 years past the perimenopausal transition prior to the initiation of any horA B neurons 250 200 150 100 50 0 Oil E2 # Figure 1.26.28 So far. increased levels of antiinflammatory cytokines (eg. These cytokines include: interleukin 6 (IL-6). and whether they undergo synapse formation with neighboring neurons. 300 #newborn . Panel B shows the mean of groups of 4 to 6 animals in each experimental group and shows that the differences are statistically significant. synaptogenesis. Cytokines in the brain perform pleiotropic functions in inflammation and are synthesized primarily by microglia and astrocytes. birth. and macrophage chemoattractant protein–1 (MCP-1). These future studies will allow us to determine whether this elevated level of neurogenesis is critical to the recovery of function. IL-10) correlate with diminished stroke severity and an improved outcome. We have found that low. Overview of the brain cell types and neuromodulators influenced by estrogens. and neuritogenesis. subcutaneous E2 generally suppresses proinflammatory cytokines. growth. IL-1β. Conversely. Panel A shows confocal micrographs of newborn neurons dual-labeled with bromodeoxyuridine and doublecortin in vehicle and estradiol-treated mice following stroke injury. Interestingly.

We found that E2 exerts profound neuroprotective action when administered immediately upon ovariectomy. Semin Neurol. These basic science and clinical studies give us a new appreciation of the breadth of estrogen actions in the adult brain to maintain function after injury or during disease. but it is clear that estradiol protects the brain from injury and enhances neurogenesis by acting to both enhance survival of neurons and stimulate the birth of new neurons. Buchanan AK. 9. in turn improve the lives of our aging population. Colton C. which will. Paganini-Hill A. A clinical trial of estrogen-replacement therapy after ischemic stroke.1134:62-69.Vol 11 . Estradiol’s anti-inflammatory actions may underpin both the protective and reparative effects. induces estrogen receptor (ER) and suppresses inflammation only if it is administered immediately after ovariectomy. Endocr Rev. Brass LM. 2. and brain: Insights from basic science and clinical studies. Figure 3. if estrogen therapy (ET) is initiated after several years of postmenopause. Our findings may help to explain the results of the WHI that reported no beneficial effect of ET against stroke because the majority of the subjects initiated ET after an extended period of hypoestrogenicity. as was the case in the Womens' Health Initiative. N Engl J Med. Suissa S. Viscoli CM.29:191-197. Carr MC. Estrogen replacement therapy and stroke. JAMA. Hurn P. Changes in estrogen receptor-alpha mRNA in the mouse cortex during development. Estradiol decreases the size of the infarct. 2006. Bake S.24:733-743. Sarrel PM. 2009 mone treatment. Bushnell CD.295:17551756. Bushnell CD. Sohrabji F. We have used ovariectomy to mimic the menopause. and simultaneously suppresses its anti-inflammatory actions. No. Neurobiol Aging.26:123-130. Wise PM. Prog Cardiovasc Dis.4:149-161. Mendelsohn ME. We hope that our growing knowledge of the pleiotropic actions of this hormone will lead to preventative and restorative therapies for neurodegenerative conditions. 1995. 2006. Prewitt AK. Studies explore stroke's gender gap. Kernan WN. This dichotomous action is due to differential actions that estradiol has when administered immediately versus when treatment is initiated after a delay (Figure 3). Maki PM. Advancing the study of stroke in women: summary and recommendations for future research from an NINDS-sponsored multidisciplinary working group. Consistently. Summary We have summarized recent studies that have increased our understanding of the complex actions of estrogens on the brain. 301 . 5. Mitka M.345:1243-1249. 4. Wilson ME. These findings strongly suggest that.37:23872399. Age-related changes in neuroprotection: is estrogen pro-inflammatory for the reproductive senescent brain? Endocrine. 10.16 These results demonstrate that a prolonged period of hypoestrogenicity disrupts both neuroprotective and anti-inflammatory actions of E2. respectively. Turgeon JL. 2006. Sohrabji F. 7. Nordell VL.5. Much more work is necessary before we fully understand the many ways through which estrogens exert beneficial actions. et al. but not when administered after 10 weeks of hypoestrogenicity. 2001. that ET will not be effective in protecting the brain against neurodegeneration. 2006. 2002. 2006.Estrogen and stroke injury . 3. 2007. 6.38:223-242. REFERENCES 1. Stroke. Wise PM. the cardiovascular system. Scarborough MM. Complex actions of sex steroids in adipose tissue. Estrogen and neuroprotection: from clinical observations to molecular mechanisms. In contrast. Dialogues Clin Neurosci.27:575-605. Brain Res. 8. E2 treatment given immediately at the time of ovariectomy attenuated central and peripheral Estrogen therapy Early Brain infarction ER expression Inflammation Overall effect Beneficial Detrimental Delayed production of proinflammatory cytokines after ischemic stroke. Horwitz RI. 3 . Estradiol protects the brain only if treatment is initiated immediately after hypoestrogenicity is induced. ❏ Acknowledgements: This work was supported by the NIH: AG02224 (PMW) and NRSA AG27614 (CMB).Wise et al Dialogues in Clinical Neuroscience . Differential effects of estrogen in the injured forebrain of young adult and reproductive senescent animals. Hormone replacement therapy and stroke: the current state of knowledge and directions for future research.29 We tested the hypothesis that an extended period of hypoestrogenicity both prevents E2 from protecting the brain against ischemia. E2 did not suppress production of proinflammatory molecules when it was administered 10 weeks postovariectomy. 2003. Dubal DB.

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Estradiol: una hormona con diversas y contradictorias acciones neuroprotectoras
Durante la última década el concepto de que los estrógenos ejercen importantes acciones neuroprotectoras ha ganado considerable atención. Hay numerosos estudios que han proporcionado una comprensión profunda de las acciones aparentemente contradictorias de los estrógenos. Actualmente se comprende más que nunca que los efectos de los estrógenos (con y sin progestinas simultáneas o en secuencia) son diversos y algunas veces opuestos. Estos efectos dependen del uso de diferentes compuestos estrogénicos y progestínicos, de las variadas vías de administración, de las diversas concentraciones, de la secuencia de tratamiento y de la edad y estado de salud de la mujer que recibe la terapia hormonal. Durante los últimos años, se ha alcanzado una mayor comprensión acerca del impacto de los estrógenos en el sistema inmune y en la inflamación. Además, se sabe que los estrógenos no sólo pueden proteger contra la muerte celular, sino que también pueden estimular el nacimiento de nuevas neuronas. Se propone que el concepto de la modulación que tienen los estrógenos sobre el sistema inmune puede ser el mecanismo básico que subyace a su capacidad de protección contra la neurodegeneración y sus poderosas acciones neurorregenerativas. Se espera que esta actualización fomente los enriquecedores diálogos entre los cientistas básicos y los clínicos para asegurar que los futuros estudios clínicos consideren muy bien la información que pueda derivarse de estudios de ciencia básica. Sólo entonces se tendrá una mejor comprensión del impacto de las hormonas en el período menopáusico y postmenopáusico en la vida de la mujer.

Œstradiol : une hormone aux actions neuroprotectrices diverses et contradictoires
Ces 10 dernières années, l’idée d’une action neuroprotectrice importante des œstrogènes a retenu particulièrement l’attention. Les actions apparemment contradictoires de ces hormones sont nettement mieux comprises grâce aux nombreuses études cliniques. Nous réalisons plus que jamais que leurs effets (avec ou sans progestatif associé de façon simultanée ou séquentielle) sont variés et parfois opposés, dépendant de l’utilisation des différents composés œstrogéniques ou progestatifs, des différents modes d’administration et concentrations, de la chronologie des traitements, et enfin de l’âge et de l’état de santé des femmes qui reçoivent le traitement hormonal. Ces dernières années, l’appréciation de l’impact des œstrogènes sur le système immunitaire et l’inflammation s’est considérablement étendue. Nous avons appris non seulement qu’ils protégeaient les cellules de l’apoptose, mais qu’ils stimulaient également la production de nouveaux neurones. Nous postulons dans cet article que la modulation œstrogénique de l’état immunitaire pourrait être le mécanisme de base qui sous-tend sa capacité protectrice contre la neurodégénération et sa puissante activité neurorégénératrice. Nous espérons que cette mise à jour encouragera un dialogue plus riche entre des scientifiques cliniciens et fondamentalistes pour s’assurer que les études cliniques futures prendront complètement en compte l’information provenant de la recherche fondamentale. C’est seulement alors que nous comprendrons l’impact des hormones sur la période de ménopause et de post-ménopause dans la vie d’une femme.

11. Solum DT, Handa RJ. Localization of estrogen receptor alpha (ER[alpha]) in pyramidal neurons of the developing rat hippocampus. Dev Brain Res. 2001;128:165-175. 12. Shughrue P, Stumpf W, Maclusky N, Zielinski N, Hochberg R. Developmental changes in estrogen receptors in mouse cerebral cortex between birth and postweaning: studied by autoradiography with 11 beta-methoxy-16 alpha-[125I]iodoestradiol. Endocrinology. 1990;126:11121124. 13. Wilson ME, Liu Y, Wise PM. Estradiol enhances Akt activation in cortical explant cultures following neuronal injury. Mol Brain Res. 2002;102:4854.

14. Bryant D, Shedahl L, Marriott L, Shapiro R, Dorsa D. Multiple pathways transmit neuroprotective effects of gonadal steroids. Endocrine. 2006;29:199-207. 15. Dubal DB, Kashon M, Pettigrew L, et al. Estradiol protects against ischemic injury. J Cereb Blood Flow Metab. 1998;18:1253-1258. 16. Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc Natl Acad Sci U S A. 2007;104:6013-6018. 17. Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci. 1999;19:6385-6393.

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Neurotoxicity of drugs of abuse—the case of methylenedioxyamphetamines (MDMA, ecstasy), and amphetamines
Euphrosyne Gouzoulis-Mayfrank, MD; Joerg Daumann, PhD

mphetamines and ring substituted methylenedioxyamphetamines are the most commonly used illicit drugs after cannabis. Amphetamines are psychostimulants, and methylenedioxyamphetamines are entactogens—psychoactive drugs with emotional and social effects. Both drug groups are derivatives of β-phenethylamine and they share chemical and pharmacological similarities (Figure 1). 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is the most popular entactogen, and methamphetamine (METH, speed) is the most popular stimulant. In Germany about 5% of young adults have used these drugs at least once.1 However, this percentage is 5 to 10 times higher among people who regularly attend parties and raves, and seems to be generally higher in other countries such as the UK and USA.2-5 Ecstasy (MDMA, 3,4-methylendioxymethamphetamine) and the stimulants methamphetamine (METH, speed) and amphetamine are popular drugs among young people, particularly in the dance scene. When given in high doses both MDMA and the stimulant amphetamines are clearly neurotoxic in laboratory animals. MDMA causes selective and persistent lesions of central serotonergic nerve terminals, whereas amphetamines damage both the serotonergic and dopaminergic systems. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies in drug users. Despite large methodological problems, the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial recovery may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive impairments with ecstasy use, particularly with memory. In contrast, studies on possible long-term neurotoxic effects of stimulant use have been relatively scarce. Preliminary evidence suggests that alterations of the dopaminergic system may persist even after years of abstinence from METH, and may be associated with deficits in motor and cognitive performance. In this paper, we will review the literature focusing on human studies.
© 2009, LLS SAS

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Dialogues Clin Neurosci. 2009;11:305-317.

Keywords: ecstasy; MDMA; methamphetamine; stimulant; amphetamine; neurotoxicity; serotonin; dopamine; memory Author affiliations: Department of Psychiatry and Psychotherapy, University of Cologne, Germany (Euphrosyne Gouzoulis-Mayfrank, Joerg Daumman); LVR Clinics of Cologne, Cologne, Germany (Joerg Daumman) Copyright © 2009 LLS SAS. All rights reserved

Address for correspondence: Professor Euphrosyne Gouzoulis-Mayfrank, MD, Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany (e-mail: e.gouzoulis@uni-koeln.de)

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Tr a n s l a t i o n a l r e s e a r c h
Selected abbreviations and acronyms
5-HT 5-HIAA DA MDMA METH SERT serotonin 5-hydroxyindoleacetic acid dopamine methylenedioxymethamphetamine (ecstasy) methamphetamine serotonin transporter nous monoamines from presynaptic terminals. The main mechanism of amphetamines is the enhanced release of dopamine (DA), particularly in the striatal system, and norepinephrine (NE). MDMA binds most strongly to the serotonin (5-HT) transporter (SERT) and induces rapid and powerful release of both 5-HT and DA. Depending on the dose and route of administration, effects of stimulants may last from 3 to about 8 hours. They include increased drive, hypervigilance, pressure of ideas and speech, euphoria, and expansive behavior, but sometimes dysphoric mood, agitation, and aggression may occur. The psychological effects of MDMA last about 3 to 5 hours, and are more complex: they include relaxation, feelings of happiness, empathy, and closeness to other people, along with stimulant-like effects, alterations of perception, and other mild hallucinogenic effects.7 The addictive potential of amphetamines is generally lower than that of cocaine or heroin, but it becomes high when the drugs are used intravenously. MDMA is considerably less addictive, and is mostly used as a recreational drug during weekends; however, a minority of about 15% to 20% of users develop a more frequent or compulsive use pattern, and they may ingest 10 or even more pills per occasion.8 Beside the issue of addiction, there is a range of acute and subacute complications including drug-induced psychoses, seizures, myocardial infarction, or stroke resulting from hypertension and/or hemorrhage, hyperpyrexia with rhabdomyolysis, disseminated intravascular coagulation (DIC) and organ failure, toxic hepatitis, and many others. Moreover,

Both ecstasy and amphetamines are easy to manufacture in underground laboratories. Ecstasy is almost always sold as tablets or pills with various imprinted logos (Figure 2). The pills typically contain 70 to 120 mg of MDMA, although the concentration may sometimes be higher or lower. Occasionally ecstasy tablets will contain similarly acting analogues (3,4-methylenedioxy-Nethylamphetamine [MDE], 3,4-methylenedioxyamphetamine [MDA], or 3,4-methylenedioxy-alpha-ethylN-methylphenethylamine [MBDB], Figure 1) or amphetamines, and more rarely they may also contain substances from different classes. Amphetamines are mostly sold as powder which can be inhaled, smoked, ingested, or injected, although intranasal use (“snorting”) is now particularly common. The acute pharmacology of MDMA and amphetamines has been widely studied.6 Among other actions, both drug groups bind to presynaptic monoamine transporters, and act as inhibitors on these sites and releasers of the endoge6 5 4 3 1 2

H NH2

-Phenethylamine

Ecstasy
R2 N O O H R1

Stimulants
CH 3 N H R R 1 = CH 3; R 2 = CH 3: MDMA R 1 = H; R2 = CH: MDA R 1 = C 2H5; R 2 = CH 3: MDE R 1 = CH 3; R 2 = C 2H5: MBDB

R = H: amphetamine R = CH 3 : methamphetamine

Figure 1. Chemical structures of amphetamines and ring-substituted methylenedioxyamphetamines (ecstasy). MDMA, methylenedioxymethamphetamine; MDE, 3,4-methylenedioxy-Nethylamphetamine; MDA, 3,4-methylenedioxyamphetamine; MBDB, 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine

Figure 2. Ecstasy pills from the illicit market.

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However. and lower 5-HT and DA transporter densities (SERT and DAT) in brain tissue. 2009 amphetamines and MDMA have been shown to be neurotoxic in animal studies. without it being critical for the essential functioning of any of these domains.17 The mechanism of neurotoxicity resulting from amphetamines and MDMA is not entirely understood. resulting in higher rates of 5-HT depletion with smaller doses of MDMA and persisting hypoinnervation patterns in most neocortical regions and the hippocampus in the range of 20% to 40% lower SERT binding depending on the brain region examined) for as long as 7 years post-treatment. and vegetative and neuroendocrine functions.6. The consequences are 5-HT and dopamine (DA) depletion.23-30 However. have confirmed the pattern of selective neurotoxicity for serotonergic axons. ie.19-20. and demonstrated persistent changes in the presynaptic striatal DA system 3 weeks after abstinence (20% lower striatal DA content.4-6 Functional consequences of neurotoxic drug regimens Generally. the long-term functional abnormalities seen in laboratory animals after neurotoxic MDMA regimens have been only subtle. full recovery was shown in most studies and most brain regions after 1 year. 40 mg/kg overall in 4 days.4 However. with the sole exception of mice. Animal studies Brain morphology and neurochemistry Several studies in different laboratories and with different species demonstrate long-term alterations in brain 5-HT systems following high and repeated doses of MDMA.13 Typical neurotoxic METH regimens are 5 to 10 mg/kg given parenterally 4 to 10 times within 1 to 4 days. 35% lower DAT binding). the lowest MDMA dose which was shown to produce longterm neurotoxic effects that persisted over months and years has been 5 mg/kg given parenterally twice daily over 4 days. particularly METH. including nonhuman primates. Stimulant-related neurotoxicity is not restricted to the serotonergic system. METH toxicity to DA and 5-HT terminals had been previously shown to be considerably more long-lasting. and reduced serotonergic axonal density in several brain regions. High and/or repeated doses of METH induce widespread degeneration of presynaptic serotonergic axon terminals and degeneration of dopaminergic terminals. reflecting reduced density of SERT. other studies reported normal 307 .Neurotoxicity of drugs of abuse . which is most prominent in the striatum.6-12 All but one species tested so far. 3 .4 The rate of recovery was shown to be region-dependent. No. stimulant amphetamines. In nonhuman primates.13-15 A recent study in vervet monkeys used an escalating-dose METH exposure which models a common human abuse pattern. with the effects being more pronounced on the striatal DA system. This probably corresponds to the very different distances that must be covered in the process of reinnervation. particularly when given at high and repeated doses. and can persist for up to 4 years after drug administration in nonhuman primates.9-11 Similarly to MDMA. but some individual studies reported only partial recovery in the hippocampus and some cortical areas and hyperinnervation in the hypothalamus. Nevertheless. sleep control. In rats. stimulus processing.Vol 11 .9-11 The alterations include depletion of 5-HT and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA).6. some studies which used specialized behavioral test methods and pharmacological challenges reported subtle functional disturbances such as increased anxiety and poor memory performance in MDMA-treated rodents and monkeys. have also been shown to be neurotoxic in rodent and nonhuman primate studies. psychological well-being. that hyperthermia enhances the formation of free radicals. Axons need to be regrown from their origin in the serotonergic cell bodies in the raphe nuclei of the brain stem to the different terminal areas of the brain. data from animal studies strongly suggest that the formation of free radicals is a key factor. sensitivity to the neurotoxic effects of MDMA was shown to be more pronounced than in rodents.21-22 Broadly speaking. reduced [3H]paroxetine binding. which exhibit neurotoxic alterations of serotonergic and dopaminergic axons.18-20 This may correspond to a complex role of the neuromodulator 5-HT in “fine tuning” and stabilizing neural transmission in cerebral networks. In the following sections we review the evidence for neurotoxicity in animal studies and in human populations. and that both hyperthermia and high ambient temperatures enhance the neurotoxic effects of the drugs. even single doses of MDMA were found to elicit some degree of serotonergic depletion lasting over a few weeks. This neurotoxic potential of the drugs may be relevant for humans.Gouzoulis-Mayfrank and Daumann Dialogues in Clinical Neuroscience . 5-HT appears to play important roles in several functional systems such as cognition. In studies with primates.16 However.

33 However.37 Rats treated with a neurotoxic regimen of METH were impaired on a radial maze sequential learning task when tested after 3 weeks. the neurotoxic doses in experimental animals are much higher than the typical human recreational doses of 20 to 40 mg of AMPH or METH. Finally.43 Hence. 36 In mice.27-28. Are the animal data relevant for humans? The key question is whether illicit drug users may suffer similar neurotoxic brain lesions as experimental animals.31-33 and studies which used behavioral tests for the assessment of anxiety and risktaking behavior yielded conflicting results. overcrowded surroundings and long periods of dancing. and 4 weeks in rodents. reduction of spontaneous locomotor activity was reported only 3 days after a neurotoxic METH regimen. they ingest up to 10 or even more pills in one night and they typically use MDMA over years. but not after 1. the extent of toxic damage and functional sequelae may well be more severe in heavy users with binge use behavior. in various cortical and subcortical regions. a study which looked at the effects of self-administration of MDMA in primates over a period as long as 18 months showed 5-HT depletions in the order of 25% to 50% lower (5-HT concentration depending on the region examined. an impairment of consolidation of learned place preference was reported after neurotoxic METH doses. a recent study reported than an escalating dose regimen which appears to mimic a common human pattern of escalating drug intake attenuates the neurotoxic effects and the OR deficits after METH treatment. leading to fur- 308 . according to some formulae for interspecies scaling.42 while studies with amphetamine users very been relatively scarce. Accordingly. neurotoxic METH regimens which are sufficient to produce neurotoxicity were shown to induce only moderate. possibly due to the small sample in this study (n=3). neurotoxicity may be enhanced by the typical conditions associated with MDMA and METH use such as hot.16. amphetamines have been used therapeutically for the treatment of attention deficit-hyperactivity disorder (ADHD) and narcolepsy for decades without clear evidence of long-term adverse effects.41 Similarly. Similarly. the interest in possible long-term sequelae of neurotoxic drug use has focused highly on MDMA. if any. in nonhuman primates progressive increases in METH doses in an escalating dose regimen induced abnormal behavior and decreases in social behavior on “injection” days with aggression decreasing throughout the study. some heavy users take MDMA more frequently than just at weekends. These moderate effects may be best explained by the fact that METH-induced degeneration of DA and 5-HT axon terminals is incomplete and that long-term reductions in monoamine concentration levels and transporter densities are in the range of 20% to 45%. however.45 Furthermore. after 3 weeks of abstinence no differences in baseline vs post-METH behaviors were observed. persisting deficits in active avoidance performance (24% increase in response latency) and balance beam performance (2to 3-fold increase in footfalls) were demonstrated. using more subtle motor tests. their absolute number is large.45 These decrements in 5-HT content did not reach statistical significance. given the widespread use of MDMA.16 These recent studies suggest that many METH users may not present with functional abnormalities despite residual dopaminergic toxicity. Although these heavy users are a minority. Compared with a neurotoxic MDMA regimen in primates (5 mg/kg twice daily over 4 days sc or ip the typical dose of a recreational MDMA weekend user (1 to 2 pills of 75 to 125 mg MDMA or analogue every 1 to 4 weeks) is still considerably lower. higher reductions in the range of 80% to 95% may be required to produce gross abnormalities such as parkinsonian-like motor deficits. Interestingly. and second. the widespread parallel use of different neurotoxic substances such as MDMA.36 Indeed. alterations in behaviour of laboratory animals.34-35 These data strongly suggest that if ecstasy users are indeed suffering neurotoxic damage to their serotonergic system. they are clearly alarming. 39-40 Interestingly. and alcohol may act synergistically and enhance the neurotoxic effects of the single drugs. METH. Nevertheless. Two reasons may account for the relatively lower interest in amphetaminerelated neurotoxicity in humans: first. which may increase the risk for long-term cumulative neurotoxic effects.44 However. 2.Tr a n s l a t i o n a l r e s e a r c h or back-to-normal performance within 2 to 3 weeks following MDMA treatment. 4 Moreover. the recreational MDMA doses might well approach doses commonly given to animals in experimental studies. however. the functional consequences may be subtle.38 and on a novelty preference object recognition (OR) task when tested after 1 week and 4 weeks. Over the last 10 to 15 years this question has received particular attention for MDMA. if the results are confirmed by further studies.

a brain area that is particularly rich in 5-HT. an ambitious and methodologically sound prospective study examined a large number of young subjects who socialized in the drug scene. even after very low dosages of ecstasy. white matter maturation.52 Recently. studies with MR spectroscopy reported higher concentration of the glia marker myoinositole with heavier use of MDMA. 5-HIAA. whereas increased regional cerebral blood volume (rCBV) in perfusion weighted imaging (PWI) may have been caused by 5-HT depletion. because they are in line with sustained effects of ecstasy on brain microvasculature. but had not yet used amphetamines or ecstasy (The Netherlands XTC Toxicity [NeXT] study). 3 . Although the novice MDMA users reported only very sporadic and low-dose use of MDMA in the follow-up period (mean 6. the MRI examinations showed decreases in rCBV in the globus pallidus and putamen (PWI).Vol 11 . No.Gouzoulis-Mayfrank and Daumann Dialogues in Clinical Neuroscience . However. and increase of apparent diffusion coefficient in the thalamus. it also exerts powerful vasoconstrictive actions on small brain vessels.48 and has been shown to stimulate neurogenesis in the hippocampus throughout adulthood. As the 5-HT concentration cannot be measured in vivo in human brains.61-64 However.62 309 . decreases in FA (indicator of axonal integrity) in the thalamus and frontoparietal white matter (DTI) and increases of FA in globus pallidus. or that it will manifest itself as an alteration of global cerebral activity in positron emission tomography and single–photon emission tomography (PET and SPECT). we may use the concentration of both 5-HT and its main metabolite.Neurotoxicity of drugs of abuse . Although relatively subtle.55 dose-dependent reductions of N-acetylaspartate (NAA) levels (NAA:creatine and NAA:choline ratios) in the frontal cortex of MDMA users. it is rather unlikely that neurotoxic damage confined to the serotonergic system will be visible in routine brain imaging procedures in terms of loss of brain volume or atrophy. another small pilot study reported a high diffusion coefficient (ADC) and high regional cerebral blood volume (rCBV) in the globus pallidus. serotonin is more than a neurotransmitter or neuromodulator in neuronal tissues. one study reported an association between longer periods of MDMA use and decreased global brain volume.49 Routine structural magnetic resonance imaging (MRI). Finally. these findings are alarming. and possibly axonal damage.47 has neurotrophic effects on brain tissue not confined to the period of brain maturation. neuroimaging was repeated in 59 incident ecstasy users and 56 matched persistent ecstasy-naives using multiple NMR techniques and SPECT for measurement of SERT availability. median 2. In addition.56 and a tendency towards lower NAA:creatine ratios in the hippocampus of MDMA users compared with controls.59 After a mean period of 17 months' follow-up. only one study reported a correlation between the 5HIAA concentration and the extent of earlier ecstasy use. perfusion and diffusion MRI. in cerebrospinal fluid (CSF) as a proxy for the concentration in the brain. a large study with 71 ecstasy polydrug users reported alterations in the thalamus asso- ciated specifically with MDMA use: decreased fractional anisotropy (FA) in diffusion tensor imaging (DTI) was suggestive of axonal loss. SPECT with 133Xe.57 These findings could be related to neurotoxic damage and glial proliferation.50 and another study54 demonstrated reduced grey matter density in several cortical regions. it is possible that the animal data demonstrating MDMA and METH-induced neurotoxicity are indeed relevant for humans.0 tablets).60 Since then several studies with larger samples showed reduced concentrations of 5-HIAA in cerebrospinal fluid of ecstasy users compared with control groups. Studies in ecstasy users Brain morphology and global brain function In principle. indicating a repair mechanism. This finding could be related to vasodilatation due to low serotonergic tone following degeneration of serotonergic axons.58 In the same study no effects of ecstasy use on apparent diffusion coefficients and brain metabolites (MR spectroscopy) were detected. and that club drug users may be exposing themselves to the risk of neurotoxic brain damage. 2009 ther increases in body temperature. An early study on a small number of ecstasy users reported normal levels of 5-HIAA in the CSF.50-53 However. and 99m Tc-hexamethylpropylene amine oxime (HMPAO) and H215O PET were generally found to be normal in ecstasy users.59 Central serotonergic parameters Reduced 5-HT concentration would be the expected outcome of widespread neurotoxic damage of serotonergic axon terminals in the brain tissue of MDMA users. In addition.46 In conclusion.0.

79-80 A causal link between these disorders and ecstasy may exist at least in a predisposed subgroup of users. Moreover. A small longitudinal study with two follow-up (+)McN5652-PET examinations confirmed the reversibility of alterations of SERT availability with a decrease in the intensity of MDMA consumption. and cognition. 310 . due to the widespread use of ecstasy and the parallel use of other substances no firm conclusion can be drawn from these reports. However.Tr a n s l a t i o n a l r e s e a r c h PET and SPECT using suitable ligands make the in-vivo examination of brain tissue receptors and/ or binding sites feasible. correlations between the SERT availability results. Hence. and were absent in former users following abstinence from MDMA use of at least 12 months. they suggest at least some degree of recovery of the assumed serotonergic lesion following abstinence.44 However. vegetative functions. differences in lifestyle) make it difficult and sometimes even impossible to draw firm conclusions from the data. after the onset of the comorbid disorder. An early PET study in 14 ecstasy users and the SERT ligand [11C] (+)McN5652 demonstrated a dose-dependent reduction in its binding.76-77 Hence. and length of abstinence periods suggested a temporary occupation or downregulation of the binding site rather than structural neurotoxic damage. processing of sensory stimuli. in the following sections we will focus on these subjects.78 and high psychiatric comorbidity was established in studies with large samples of ecstasy-experienced polydrug users. The majority of studies report on psychopathology and cognition. There are several anecdotal reports of depressive syndromes.65 A further study in 10 ecstasy users also demonstrated reduced cortical SERT availability using SPECT and the SERT ligand β-CIT. polydrug use. and psychotic episodes associated with ecstasy use. Such subtle residual changes could be functionally important. alterations were less pronounced in male users.75 This pattern is in line with animal data showing temporary (up to 1 month) downregulation of postsynaptic 5-HT2 receptors resulting from high synaptic 5-HT concentration after administration of MDMA.73 All in all.74 In summary. another SPECT study with the 5-HT 2A receptor ligand [123I]-R91150 demonstrated reduced cortical binding in current ecstasy users with short-term abstinence and increased binding in former users who had not used ecstasy for an average of 5 months. these studies indicate that women may be more susceptible to MDMAinduced alterations of the serotonergic system than men.81 Several studies used standardized psychometric instruments and demonstrated higher scores for impulsiveness. Nevertheless. Consequently. unlike the SERT data. in most cases. aggressiveness. but demonstrated that the use of ecstasy started.58-68-72 and only one small study with 12 former MDMA users was negative. postsynaptic receptor data suggest that alterations of serotonergic systems may persist over long periods of time in abstinent MDMA users. all but one more recent studies with refined methods67 and larger samples (up to 61 current and former users68) confirmed reduced SERT availability at least in female current users with a relatively heavy use pattern (>50 pills). and long-lasting upregulation of the same postsynaptic receptors following widespread presynaptic damage of serotonergic neurons leading to 5-HT depletion. and differences favor the control groups in almost every study. in addition. sleep architecture. and might contribute to clinical or subclinical alterations of psychological well-being and behavior of ecstasy users. results have been inconsistent and several methodological problems (eg. particularly with depression. damage to the central serotonergic system could be theoretically followed by disturbances in different fields such as psychological well-being. suicidality. pre-existing differences.66 Since then there has been some debate on the validity of SPECT and PET techniques with SERT ligands in measuring MDMA-related neurotoxicity and on additional subject-related methodological problems of these early studies. both globally and in most cortical and subcortical brain regions examined.66 However. Serotonin-related functions The neuromodulator 5-HT is involved in several functional systems of the CNS. Interestingly. and. and impulsiveness. neuroendocrine secretion. Psychopathology A low serotonergic tone has been widely associated with psychological disturbances. anxiety. cumulative ecstasy consumption. In the last 10 to 12 years there have been numerous studies demonstrating group differences between ecstasy users and controls in virtually all these fields. results from a prospective-longitudinal investigation on a large representative sample of adolescents and young adults (n=2462) over 4 years confirmed a high psychiatric comorbidity in MDMA users.

and their results have been similar. although a minority of studies reported an association of memory deficits with the extent of the parallel use of cannabis or the combination of ecstasy and cannabis.89 In conclusion.44 However. anxiety. results have not been entirely consistent.44-92 The consistency of the data on memory functions and the association of performance with the extent of previous ecstasy use are highly suggestive of a residual neurotoxic effect of MDMA. in recent studies with relatively large samples of 234. three studies in current and former MDMA users with an abstinence period of several months or even years reported similar or even poorer memory performance in the former MDMA users.70. it is still unclear whether the frequently reported emotional instability and impulsive features and/ or the overall high level of psychological distress result from ecstasy use or from the combined use of several substances. 84 Finally. elevated psychopathology appeared to be associated with polydrug use in general and not specifically with ecstasy use. No.87 Finally. episodic memory and learning. in a recent study with a longitudinal design and a follow-up period of 18 months increases in self-rated psychopathology were associated with continued cannabis rather than continued ecstasy use.44. 61.92 To date. poor memory was associated with a heavier pattern of ecstasy use. another study suggests an interaction between genetic factors and the effects of MDMA use on mood (high depression scores only in ecstasy users carrying the s allele of the SERT encoding gene but not in users with the ll genotype). 3 . Interestingly. for example.Gouzoulis-Mayfrank and Daumann Dialogues in Clinical Neuroscience .68.90-91 Indeed. the linkage between ecstasy-induced neurotoxicity and psychological problems does not seem to have been established at this stage. rather than the use of ecstasy alone.87 In this study.27-28. or whether alternatively these are factors predisposing to a general affinity to drugs.88 These findings underline the complexity of the issue and are in line with animal data showing different long-term effects of MDMA on anxiety in rats depending on the level of their baseline anxiety. but elevated depression scores in current and former users. novelty seeking. and an overall heightened level of psychological distress in mostly polydrug ecstasy users compared with control groups. poorly matched control groups.99 although SERT availability was only reduced in current 311 . as well as increased cognitive impulsivity and diminished executive control. the most consistent finding is that of subtle deficits in episodic memory and learning abilities.44. hostility/ aggression. and lack of toxicological analyses for verification of the subjects’ reports. higher depression scores were associated with higher lifetime MDMA dose.68. and only a loose association between the neurotoxic effects of MDMA and its long-term impact on anxiety-related behavior. Numerous cross-sectional studies demonstrated relative impairments of learning and memory performance and only a small minority of studies reported no differences between ecstasy users and controls or small and insignificant differences after adjusting for possible confounders. these results have been less consistent.11 and a stimulatory role of 5-HT for neurogenesis in the hippocampus. but there was no association of psychometric scores with SERT availability. 2009 depressive mood.94-96 Although several studies and particularly the earlier studies suffered from significant methodological limitations such as polydrug use.85-86 All in all. relative deficits of short-term or working memory. there are indications that serotonergic neurotransmission may particularly interfere with an individual's cognitive style (impulsive vs systematic) as well as with memory and learning processes.49 Interestingly. were frequently reported in ecstasy users. It is possible that the hippocampus may be particularly vulnerable to the neurotoxic effects of MDMA.Neurotoxicity of drugs of abuse . Cognition Although our understanding of the role of serotonin in cognitive processes is incomplete.44.44 Elevated cognitive impulsivity and diminished executive control were also demonstrated in some studies. short abstinence periods. emotional instability. and 50 polydrug ecstasy users and controls using other drugs only.Vol 11 . and this may explain why residual effects are most consistent in the memory domain. however.92-93 In general.97-98 This interpretation is in line with the animal experimental data. one study reported reduced impulsiveness and aggression compared with the control group. a recent combined SPECT and psychometric study established decreased SERT availability only in current MDMA users.63 Two studies suggested a link between high scores and heavy parallel cannabis use. which demonstrated particularly strong and long-lasting neurotoxic effects of MDMA in the hippocampus.4. a number of more recent investigations were carefully designed and conducted.82-83 Moreover.

This view would be in line both with findings of a dose-dependent memory deficit in cross-sectional studies comparing ecstasy users with control samples. but remained low in the striatum. reduced DAT density. In addition.5 tablets) they failed to demonstrate retest improvements in verbal memory shown by the persistent MDMA-naive group of 60 subjects. and reduced dopamine D2 receptors in the striatum. the linkage between ecstasy use and memory decline is considered probable at this stage. the functional consequences of neurotoxic lesions observed following a threshold use of ecstasy may manifest themselves in binary (yes/no) manner. longterm negative consequences are conceivable. median 1. lower levels of SERT density and vesicular monoamine transporters (VMAT2) across striatal subregions. Initial small studies with PET (regional glucose metabolic rate (rMRGlu).106 In a preliminary longitudinal study in five former speed users. and altered brain glucose metabolism in the limbic and orbitofrontal regions of METH users. but the number of publications has been constantly increasing over 312 . were followed up and reexamined after a mean period of 3 years' follow-up. the last few years. 103 Although the 58 novice MDMA users reported only very sporadic and low-dose use of MDMA in the followup period (mean 3. as shown in primate studies.104-109 Reduced levels of striatal DAT were found in former METH users even 3 years or more after last use.112 Finally. findings from the only prospective study to date do support this view (part of the Netherlands XTC Toxicity [NeXT] study).114 Theoretically. but they normalized after 1 year of abstinence. and D2 receptor availability).109 Two recent larger MR spectroscopy studies with 24110 and 36111 currently abstinent METH users reported low levels of the neuronal marker NAA (NAA/creatine ratio) in the anterior cingulate even after very long periods of abstinence of several years.102 Finally.11 regeneration of serotonergic axons may take a long time and may remain incomplete. caudate. During this follow-up period the initially reduced MRGlu rose in the thalamus.103 This finding suggests that even very low MDMA doses may be associated with persisting alterations in memory and learning functions. and psychopathologi- Studies in amphetamine users Compared with MDMA. but had not yet used amphetamines or ecstasy. the literature on amphetamine related neurotoxicity in humans is limited. This finding suggests that following cessation of METH use. which may contribute to some degree of normalization of neuronal structure and function.110 A structural MRI study in 22 METH users and 21 controls revealed smaller hippocampal volumes and significant white-matter hypertrophy in the METH group.113 A recent review of the literature reported enlarged striatal volumes.68-70 Two longitudinal studies yielded conflicting results: a small study in 15 ecstasy users reported memory decline after continued use and improvement after abstinence over 36 months. within the METH group larger basal ganglia volumes were associated with better cognitive performance and less cumulative METH usage.102 Although these results may be interpreted as evidence against neurotoxicity-related memory decline. the choline/NAA values were abnormally high in the users with relative short abstinence time.110 In contrast. and nucleus accumbens.113 Interestingly. reduced concentrations of the neuronal marker NAA-acetylasparate and total creatine in the basal ganglia. DAT.104 and they were found to be associated with a longer duration of speed use. cognitive. SPECT (DAT availability) and MR spectroscopy techniques suggested that heavy use of stimulants may also be neurotoxic in humans and that alterations may persist over prolonged periods of time. Therefore. the authors argued that the enlarged putamen and globus pallidus might represent a compensatory response to maintain function.Tr a n s l a t i o n a l r e s e a r c h users. A large number of young subjects who socialized in the drug scene. In conclusion.2.100-101 but a larger study in 38 ecstasy users reported no further deterioration of memory performance after continued use and no improvement after abstinence over 18 months. Compensatory neural mechanisms that might develop could possibly explain the absence of functional deterioration despite subsequent “enlargement” of the neurotoxic lesions. and with the finding of stable performance in the larger within-subject longitudinal study. the largest cross-sectional study so far demonstrated enlarged putamen and globus pallidus in 50 METH users compared with 50 controls. Although the clinical relevance of this subtle finding is clearly limited. adaptive changes occur. rMRGlu was assessed after 6 months and again after 12 to 17 months of abstinence. neurotoxic dopaminergic lesions could be associated with motor. it is still possible that memory deficits in ecstasy users persist even after 18 months of abstinence because.

❏ REFERENCES 1. However.Vol 11 . but not in controls. Illegale Drogen. dopaminergic parameters.4-methylenedioxymethamphetamine (MDMA. 2003.S1:1928. Similarly. J Adolesc Health. 3 . Moreover.51. 2001.” Further longitudinal and prospective studies are clearly needed. there are early indications that at least heavy METH use may also be followed by alterations in brain structure. Orth. It's a rave new world: estimating the prevalence and perceived harm of ecstasy and other drug use among club rave attendees.Gouzoulis-Mayfrank and Daumann Dialogues in Clinical Neuroscience . increased Stroop interference) was shown to correlate with levels of NAA-Cr within the anterior cingulate in METH users. and cognitive function. polydrug use and the typical environment of use (hot. it is not clear whether these deficits are a consequence of the use of stimulants or whether they reflect pre-existing low cognitive abilities in people who become drug users later in life. et al. reduced attentional control (ie. Tossmann P. Elliott JM. extensive physical exercise in the form of dancing) may well potentiate the neurotoxic effects of the drugs. 3. several cases with severe deficits have also been reported. particularly in the memory and learning domain. 2. Conclusions Ecstasy (MDMA) and stimulant amphetamines (METH and AMPH) are popular drugs of abuse and they are neurotoxic in animal studies. 2005. even after minimal exposure to MDMA. reduced DAT densities and longer duration of METH use were associated with poorer performance in both fine motor and memory tasks in 15 currently abstinent METH users. et al. Green AR. Yacoubian GS. Eur Addict Res. Similarly. High and repeated doses of MDMA cause selective and long-lasting degeneration of 5-HT axon terminals in several brain regions. especially in heavy users with binge use patterns. Einstiegsalter und Trends. 313 . "ecstasy"). In addition.33:187-196. Lee JE. 2003. more subtle motor deficits were reported in two studies.109 The literature on long-term psycho(patho)logical sequelae of stimulant use is inconclusive. whereas METH and AMPH damage both serotonergic and dopaminergic neurons. Nevertheless.111. and even heavy users initially appear mostly unimpaired in their everyday life. Harding CA. The use of drugs within the techno party scene in European metropolitan cities.44 Regarding METH-induced neurotoxicity.59. Boldt S. frontal executive control. J Drug Educ. B.116-122 However. Mechan AO. were also found to be associated with ecstasy use. Sucht. Pharmacol Rev. To date. the only prospective study to date demonstrated structural brain alterations and subtle memory dysfunction. gross motor disturbances have not been demonstrated in METH users. the limited evidence to date suggests that persisting neurotoxic brain damage is conceivable in METH users. and noisy rooms. 5. cross-sectional studies in chronic stimulant users demonstrated relatively low performance in short-term and episodic memory.106. Tensil MD. the message we have to convey to young people in information campaigns is: “MDMA and amphetamine neurotoxicity for humans is not yet proven.103 Although most ecstasy users do not suffer cognitive impairment of clinically relevant proportions. subtle cognitive dysfunctions. To date.55:463-508. Boyle C. Although the results are not entirely consistent.109 Finally. the normalization of rMRGlu in the thalamus was associated with an improvement of motor and memory performance after long-term abstinence of 1 year and more.Neurotoxicity of drugs of abuse . 2009 cal abnormalities. No. Augustin R.30:64-72. Increasing MDMA use among college students: results of a national survey.115 However. Although the doses taken recreationally are considerably lower than the doses typically given in animal studies. Kraus L. 2002. and planning abilities.. The pharmacology and clinical pharmacology of 3. More studies with longitudinal and prospective designs are clearly needed. Studies with drug users demonstrated associations of subtle alterations in brain structure and 5-HT brain parameters with MDMA use. there is concern that the memory deficits of ecstasy users—although subtle and mostly subclinical— and the possible underlying hippocampal dysfunction might help accelerate the normal brain ageing process and constitute a risk factor for earlier onset and/or more severe age-related memory decline in later years. but it is highly likely. these associations were replicated in many welldesigned. 123-124 Moreover. In light of the popularity of ecstasy and stimulants among young people. overcrowded. evidence from studies with drug users is relatively scarce and still preliminary.106 Also. questions around their neurotoxic effects on the brain remain highly topical.7:2-23. 4. Ergebnisse des Epidemiologischen Suchtsurvey 2003. controlled studies including longitudinal and one prospective investigation. Wechsler H. Strote J. some users exhibit compulsive binge use behaviors that may well correspond to the ani- mal doses. Jr.111 In conclusion.

Ces dernières années. Borchardt D. Fleckenstein AE.19:5096-5107. 'Ecstasy'). Quinton MS. éxtasis) y las anfetaminas estimulantes El éxtasis (MDMA. J Pharmacol Exp Ther. En este artículo se revisará la literatura dedicada a estudios en humanos.Tr a n s l a t i o n a l r e s e a r c h Neurotoxicidad de las drogas de abuso: el caso de las metilendioxianfetaminas (MDMA. 2004. Wlos J. J Neurosci.261:616-622.15:5476-5485. Seiden LS. Hatzidimitriou G. les études sur les éventuels effets neurotoxiques à long terme de la consommation de stimulant sont relativement rares. 9. “speed”) y anfetamínicos son drogas frecuentes entre los jóvenes. 3.4-methylenedioxyethylamphetamine). Fischer C. Ricaurte GA. A case of toxic psychosis induced by 'eve' (3. especialmente en lugares de baile. La MDMA provoque des lésions sélectives et persistantes des terminaisons nerveuses centrales sérotoninergiques et les amphétamines lèsent à la fois les systèmes sérotoninergique et dopaminergique. des séquelles fonctionnelles peuvent persister. et al. 6. y los estimulantes metanfetamínicos (METH. même après des années d’abstinence de METH. 11. À l’opposé.4methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. même après un arrêt prolongé. aunque puede conseguirse cierta recuperación parcial después de una abstinencia prolongada. 8. Chronic tolerance to recreational MDMA (3. 4-methylenedioxymethamphetamine (MDMA. 1992. 14.112-113:143-146.4 metilendioximetanfetamina). Cuando el MDMA los estimulantes anfetamínicos son administradas en altas dosis a animales de laboratorio resultan claramente neurotóxicas. Hanson GR.163:251-276. Hermle L. 3. la amplia evidencia sugiere que existen alteraciones residuales de la transmisión serotoninérgica en usuarios de MDMA. persistance qui peut être associée à des déficits des performances motrices et cognitives. Ricaurte GA. surtout dans les milieux festifs. 1999. Hatzidimitriou G. 314 . Ricaurte GA. mientras que las anfetaminas dañan tanto los sistemas serotoninérgicos como dopaminérgicos. Reorganization of ascending 5-HT axon projections in animals previously exposed to the recreational drug (+/-)3. Methamphetamine and methylenedioxymethamphetamine neurotoxicity: possible mechanisms of cell destruction. 7. nous passons en revue la littérature centrée sur les études chez l’homme. Lasting effects of (+-)-3. Toxicol Lett. et al. speed) et amphétaminiques sont des drogues courantes chez les jeunes. Des résultats préliminaires montrent que les modifications du système dopaminergique persistent. ecstasy) et des amphétamines stimulantes L’ecstasy (MDMA. Rau KS. Dans cet article. l’essentiel des arguments sont en faveur de modifications résiduelles de la transmission sérotoninergique chez les consommateurs de MDMA. especialmente las alteraciones de memoria con el uso de éxtasis. Neuropharmacology. la MDMA et les amphétamines stimulantes sont clairement neurotoxiques. AAPS J. J Psychopharmacol. 10. Katz JL. El MDMA produce lesiones selectivas y persistentes de los terminales nerviosos serotoninérgicos centrales. En contraste. Malgré d’importants problèmes méthodologiques. 1993.4methylenedioxymeth¬amphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. McCann UD. 1995. Gouzoulis E. Martello AL. En los últimos años la pregunta acerca de la neurotoxicidad inducida por el éxtasis y las posibles secuelas funcionales ha sido tema de algunos estudios con usuarios de drogas. surtout mnésiques. 1996. Amphetamine neurotoxicity: accomplishments and remaining challenges. Sabol KE. 3.27:821-826. Szabo Z. Toxicodynamics and long-term toxicity of the recreational drug. 2005.19:71-83.50:75. et al. 2000. Arch Gen Psychiatry. The methamphetamine experience: a NIDA partnership. J Neurosci. Parrott AC. Yamamoto BK. los estudios acerca de los posibles efectos neurotóxicos a largo plazo por el uso de estimulantes han sido relativamente escasos. Neurosci Biobehav Rev. Sin embargo. NIDA Res Monogr.47 (suppl 1):92-100. las secuelas funcionales pueden persistir aun después de largos períodos de abstinencia. Neurotoxicité des substances à l’origine d’abus: cas des méthylènedioxyamphétamines (MDMA. A pesar de los grandes problemas metodológicos. Cependant.4-méthylènedioxyméthamphétamine) et les stimulants méthamphétaminiques (METH. 15. plusieurs études ont traité la question de la neurotoxicité de l’ecstasy et des séquelles éventuelles chez les consommateurs de cette drogue. La evidencia preliminar sugiere que las alteraciones del sistema dopaminérgico pueden persistir aun después de años de abstinencia de METH y pueden asociarse con déficit en el rendimiento motor y cognitivo. récupérables en partie après une longue abstinence. Causes and consequences of methamphetamine and MDMA toxicity. "ecstasy").8:E337-E347. McCann UD. 13. 2004. Altered serotonin innervation patterns in the forebrain of monkeys treated with (+/-)3. Administrées à dose élevée à des animaux de laboratoire. Ricaurte GA. los hallazgos más consistentes asocian los deterioros cognitivos leves.4-methylenedioxymethamphetamine) or Ecstasy. 2006. Aujourd’hui les résultats les plus constants font état de déficits cognitifs subtils avec l’ecstasy.4-methylenedioxymethamphetamine (MDMA. A la fecha. 12. McCann UD.

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PhD.de) www. kynurenine.3-dioxygenase and in the tryptophan-kynurenine metabolism. Markus J. 2009. MD. Although the roles of dopamine in schizophrenia and of serotonin and noradrenaline in depression have been studied intensively. Ludwig-Maximilians-Universität. In MD.uni-muenchen.11:319-332. the exact underlying pathological mechanisms of both disorders are still unclear. inflammation. which may contribute to an excessive agonist action of N-methyl-D-aspartate (NMDA) in depression and of NMDA antagonism in schizophrenia. DipPsych. opposing patterns of type-1 vs type-2 immune response seem to be associated with differences in the activation of the enzyme indoleamine 2. COX-2 inhibitors have been tested in animal models of depression and in preliminary clinical trials.Pharmacological aspects The impact of neuroimmune dysregulation on neuroprotection and neurotoxicity in psychiatric disorders—relation to drug treatment Norbert Müller. Department of Psychiatry and Psychotherapy. Germany (e-mail: norbert. MD. cerebrospinal fluid (CSF). however. resulting in increased production of kynurenic acid in schizophrenia and decreased production of kynurenic acid in depression. PhD here is no doubt that dopaminergic. different patterns of immune activation may also lead to an imbalance between the neuroprotective and the neurotoxic effects of the tryptophan/kynurenine metabolism. pointing to favorable effects in schizophrenia and in MD. Regarding the neuroprotective function of kynurenic acid and the neurotoxic effects of quinolinic acid (QUIN). and in imaging and postmortem studies of depressed An inflammatory pathogenesis has been postulated for schizophrenia and major depression (MD). Schwarz. In schizophrenia and depression. glutamatergic hyperfunction seems to be closely related to the lack of serotonergic and noradrenergic neurotransmission. partly correct the immune imbalance and the excess production of the neurotoxic QUIN.org 319 . MD. PhD. serotonergic. The differential activation of microglia cells and astrocytes may be an additional mechanism contributing to this imbalance. LLS SAS T Dialogues Clin Neurosci. 80336 München. LudwigMaximilians-Universität München. The immunological imbalance results in an inflammatory state combined with increased prostaglandin E2 production and increased cyclo-oxygenase-2 (COX-2) expression.dialogues-cns. Altered glutamate levels have been observed in the plasma. Germany Copyright © 2009 LLS SAS. Aye-Mu Myint.mueller@med. 7. © 2009. serum. All rights reserved Address for correspondence: Prof Dr med Dipl-Psych Norbert Müller. major depression. Nußbaumstr. These differences are associated with an imbalance in the glutamatergic neurotransmission. therapy Author affiliations: Department of Psychiatry and Psychotherapy. and/or noradrenergic neurotransmission play an important role in the pathophysiology of major depression (MD) and schizophrenia. Keywords: schizophrenia. The immunological effects of many existing antipsychotics and antidepressants.

TH-1 cells produce the characteristic “type-1” activating cytokines such as interleukin (IL) -2 and interferon (IFN)-γ. Table II.and B-cells Inflammation in schizophrenia and depression Infection during pregnancy in mothers of offspring who later develop schizophrenia has been repeatedly described. Proinflammatory cytokines. tumor necrosis factor. interleukin. which both seem to play a key role in the pathophysiology of schizophrenia and MD. dopaminergic hyperfunction in the limbic system and dopaminergic hypofunction in the frontal cortex are thought to be the main neurotransmitter disturbances.Pharmacological aspects Selected abbreviations and acronyms COX IDO IL KYN KYNA MD QUIN TDO TNF cyclo-oxygenase indoleamine 2. TH-2 or certain monocytes/macrophages (M2) produce mainly IL4. including the innate immune system. The type-1 immune system promotes the cell-mediated immune response directed against intracellular pathogens. IL-6 activates the type-2 response including the antibody production. including the production of antibodies directed against extracellular pathogens. in particular in the second trimester.2 whereas glutamatergic hyperfunction acts through low NMDA antagonism in the kynurenine pathway in MD. activating other cellular components of the inflammatory response. in contrast. interferon. acute-phase protein. IL.3-dioxygenase interleukin kynurenine kynurenic acid major depression quinolinic acid tryptophan 2. 320 . Type-1 and type-2 cytokines antagonize each other in promoting their own type of response. While TNF-α is an ubiquitiously expressed cytokine mainly activating the type-1 response. IL-10. while suppressing the immune response of the other. Cytokines regulate all Components Cellular Innate Monocytes Makrophages Granulocytes Natural killer cells γ/δ-cells Complement. natural killer (NK) cells and monocytes as the first barrier of the immune system being part of this. The glutamatergic system is closely related in function to the immune system and to the tryptophankynurenine metabolism. The adaptive immune response with the antibody-producing B-lymphocytes. therefore the term “polarized” can be used. mannose-binding lectin Adaptive T.5 The immune response and type-1 and type-2 polarization The innate immune system is phylogenetically the oldest part of the immune response. TNF. (Tables I and II). T-helper-1 (TH-1) and T-helper-2 (TH-2). antibodyproducing arm of the adaptive immune system is mainly activated by the type-2 immune response.6 Further terminology separates the cytokines into proinflammatory and anti-inflammatory types.3 Glutamatergic dysfunction seems to be a common pathway in the neurobiology of schizophrenia and depression. Recent research provides further insight that glutamatergic hypofunction might be the cause for this dopaminergic dysfunction in schizophrenia. the immune response is called the type-1 immune response. 7. and IL-13.3-dioxygenase tumor necrosis factor types and all cellular components of the immune system. such as tumor necrosis factor α (TNF-α) and IL-6 are primarily secreted from monocytes and macrophages. Cytokines of the polarized immune response. whereas the type-2 response helps B-cell maturation and promotes the humoral immune response. but also certain monocytes/macrophages (M1) and other cell types produce these cytokines.8 The Type-1 IL-2 IL-12 IFN-γ IL-18 (TNF-α) Type-2 IL-4 IL-13 [IL-10] Cytokines Humoral Antibodies Table I. the T-lymphocytes and their regulating “immunotransmitters. Helper T-cells are of two types.1 In schizophrenia.” the cytokines. The humoral. Antiinflammatory cytokines such as IL-4 and IL-10 help to downregulate the inflammatory immune response. Components of the unspecific “innate” and the specific “adaptive” immune systems in humans.4. since not only TH-1 cells. is the specifically acting component of the immune system. patients. However. IFN.

20 The decreased response of lymphocytes after stimulation with specific antigens reflects a reduced capacity for a type-1 immune response in schizophrenia.15 An inflammatory model of MD is “sickness behavior. depressed mood. and IFN-γ. anxiety. 7. the involvement of cytokines in the regulation of the behavioral symptoms of sickness behavior has been studied by application of the bacterial endotoxin lipoploysaccharide (LPS) to human volunteers. Type-1 and type-2 immune responses in schizophrenia A well established finding in schizophrenia is the decreased in vitro production of IL-2 and IFN-γ. The sicknessrelated psychopathological symptoms during infection and inflammation are mediated by proinflammatory cytokines such as IL-1. malaise. only increases of IL1 receptor antagonist serum levels and of IL-6 serum levels were found. which is associated with: -A decreased availability of tryptophan and serotonin -A disturbance of the kynurenine metabolism with an imbalance in favour of the production of the NMDA receptor agonist quinolinic acid (QUIN) -An imbalance in astrocyte and microglial activation associated with increased production of QUIN.27 After including antipsychotic medication effects into the analysis.26 The latest meta-analysis showed dominant proinflammatory changes in schizophrenia but not involving Th2 cytokines.11.18. as well. a product of activated monocytes/macrophages. Decreased levels of the soluble (s) intercellular adhesion molecule-1 (ICAM-1).10 These data were confirmed in recent studies.24 This finding could be replicated in unmedicated schizophrenic patients using a skin test for the cellular immune response. as opposed to any single pathogen.25 However.28 IL-6 serum levels might be especially 321 . seems to play a role in schizophrenia and in MD. Several reports described increased serum IL-6 levels in schizophrenia. lethargy. was found to induce mild fever. Effects of antidepressants on the immune function support this view. there are some conflicting results regarding increased levels of Th1 cytokines in schizophrenia. Type-1 parameters. Sickness behavior is characterized by weakness. 16 LPS.Neuroimmune dysregulation in psychiatric disorders . and cognitive impairment. TNF-α.7 A fivefold increased risk for developing psychoses later on was detected after infection of the central nervous system (CNS) in early childhood. too. listlessness. caused by infection or by other mechanisms.Vol 11 .21 intracellular adhesion molecule (ICAM)-1 is a type-1 related protein and a celladhesion molecule expressed on macrophages and lymphocytes.3-dioxygenase (IDO) in the CNS. but the specific mechanisms underlying the heterogeneous disease MD are not yet fully understood.” the reaction of the organism to infection and inflammation. may be related to the increased risk for schizophrenia in the offspring. were not included in the meta-analysis. 2009 maternal immune response itself. also represent an underactivation of the type-1 immune system. 3 . because only a few studies have been performed in unmedicated patients. a potent activator of proinflammatory cytokines. Inflammation.12. hypothesized to be downregulated in schizophrenia. and reduced food intake— all of which are depression-like symptoms.23 A blunted response of the skin to different antigens in schizophrenia was observed before the era of antipsychotics. The levels of anxiety. Decreased levels of neopterin. increased IL-8 levels of mothers during the second trimester were associated with an increased risk for schizophrenia in the offspring. as found in schizophrenia.22 Decreased levels of the soluble TNFreceptor p55—mostly decreased when TNF-α is decreased—were observed. there is a strong relationship between the cytokine and the neurotransmitter systems. 13 Signs of inflammation were found in schizophrenic brains.9 Indeed. IL-6. inability to concentrate.Müller et al Dialogues in Clinical Neuroscience . No.19 reflecting a blunted production of type-1 cytokines. depression. and cognitive impairment were found to be related to the levels of circulating cytokines. also point to a blunted activation of the type-1 response. Undoubtedly.17 Mechanisms that may contribute to inflammation and cause depressive states are: • A direct influence of proinflammatory cytokines on the serotonin and noradrenaline metabolism • An imbalance of the type-1—type-2 immune response leading to an increased tryptophan and serotonin metabolism by activation of indoleamine 2.14 and the term “mild localized chronic encephalitis” to describe a slight but chronic inflammatory process in schizophrenia was proposed. In humans. The mechanisms and the therapeutic implications will be discussed below. decreased interest in the surroundings. anorexia. The active pathway of these cytokines from the peripheral immune system to the brain is via afferent neurons and through direct targeting of the amygdala and other brain regions after diffusion at the circumventricular organs and choroid plexus.

42 The increased plasma concentrations of the proinflammatory cytokines IL-1 and IL-6 observed in depressed patients was found to correlate with the severity of depression and with measures of the hypothalamus-pituitary-adrenal (HPA)-axis hyperactivity. smoking.47 By this mechanism. Increased sIL-2R levels reflect an increased production of IL-2. the genetics of the immune system in relation to MD has also been investigated. In a small study. The plasma levels and CNS expression of ICAM-1 are associated with depressive symptoms in patients treated with IFN-γ.50 Since different pathologies may underlie the syndrome of depression. Increased proinflammatory type-1 cytokines in major depression Characteristics of the immune activation in MD include increased numbers of circulating lymphocytes and phagocytic cells. etc. different types of MD were observed to exhibit different immune profiles: the subgroup of melancholic depressed patients showed a decreased type-1 activation—as observed in schizophrenic patients40—while the nonmelancholic depressed patients showed signs of inflammation such as increased monocyte count and increased levels of α2-macroglobulin.41. and promotes the influx of peripheral immune cells through the blood-brain barrier.40 Neopterin is a sensitive marker of the cell-mediated type-1 immunity.42 and the IFNγ/IL-4 ratio.48 and increased expression of ICAM-1 was found in the prefrontal cortex of elderly depressed patients. IL-2.45 Data on IL-2 in MD are mainly restricted to the estimation of its soluble receptor sIL-2R in the peripheral blood. However.39 Increased expression of ICAM-1 is observed in inflammatory processes.32 The key cytokine of the type-2 immune response is IL4.42.Pharmacological aspects high in patients with an unfavorable course of the disease. chronicity. since clinical studies have observed higher levels of type-1 cytokines in suicidal patients. although studies are conflicting. and some authors refer to it as a marker of the type-2 immune response. accompanied by lower plasma tryptophan availability were described. 45 Higher plasma levels of IFN-γ in depressed patients. the data show that the immune response in schizophrenia can be confounded partly by factors specific to the disease such as its duration. upregulated serum levels of indicators of activated immune cells (neopterin. The main sources of neopterin are monocytes/macrophages. as well as increased release of proinflammatory cytokines.31. and higher serum concentrations of positive acute phase proteins (APPs). however. Indeed. TNF-α and IL6 through activated macrophages and IFN-γ through activated T-cells. Moreover. several other signs of activation of the type-2 immune response are described in schizophrenia.49 In late-life depression. Increased levels of IL-4 in the CSF of juvenile schizophrenic patients have been reported. distinct associations between suicidality and type-1 immune response and a predominance of type-2 immune parameters in nonsuicidal patients were observed.32-39 Increased numbers of peripheral mononuclear cells in MD have been described by different groups of researchers.32 In the CSF.51 An epidemiological study 322 . including increased Th2 type of lymphocytes in the blood.45. In contrast to schizophrenia.33 which indicates that the increased type-2 response in schizophrenia is not only a phenomenon of the peripheral immune response. observed in a very high proportion of depressed patients. in genes coding for IL1 and TNF-α may confer a greater susceptibility to develop MD.43. such as IL-1. 44 As genetics plays a role in MD. The blood levels of sIL-2R were repeatedly found to be increased in MD patients. a marker for Th1/Th2 balance is also higher in depressed patients. macrophages and costimulatory lymphocytes can invade the central nervous system (CNS). Particular cytokine gene polymorphisms. and an increase in IL-10 serum levels. or therapy response. seems to be an example of the immune activation pattern in depression. there are conflicting results. Increased sICAM-1 levels were observed in patients with more depressive symptoms. 46 The production of IL-2 and IFN-γ is the typical marker of a type-1 immune response. different immunological states might be involved.40 Suicidality. IFN-γ is produced in greater amounts by lymphocytes of patients with MD than of healthy controls. soluble IL-2 receptors). and partly by other factors such as antipsychotic medication.29 IL-6 is a product of activated monocytes. In accordance with the findings of increased monocytes/macrophages. eg. coupled with reduced levels of negative APPs. further increasing the proinflammatory immune response.30 increased production of immunoglobulinE (IgE). IL-10 levels were found to be related to the severity of the psychosis. an increased secretion of neopterin has been described by several groups of researchers.

57 The increase of TNF-α and TNF-α receptors during therapy with clozapin was observed repeatedly. 63 Several antidepressants seem to be able to induce a shift from type 1 to type 2.62. the blunted reaction to vaccination with Salmonella typhii was not observed in patients medicated with antipsychotics. since the ability of three antidepressants (sertraline.73 Over 30 years ago it was suggested that antidepressants inhibit PGE2. in other words from a proinflammatory to an anti-inflammatory immune response. Regarding the type-2 response.58 Moreover.52 Increased levels of serum sIL-2R have been described in medication-free suicide attempters. showing no effect of antidepressants to the in-vitro stimulation of cytokines (overview. irrespective of the psychiatric diagnosis. an increase of sIL-2R— the increase reflects an increase of activated.63 A downregulation of the IL-6 production was observed during amitriptyline treatment.55 Additionally. however. and trazodone) to greatly reduce the IFNγ/IL-10 ratio was shown in vitro. Therapeutic techniques in depression are associated with downregulation of the proinflammatory immune response Antidepressant pharmacotherapy A modulatory.53 and treatment with high-dose IL-2 has been associated with suicide in a case report.22 and the ICAM-1 ligand leukocyte function antigen-1 (LFA-1) shows a significantly increased expression during antipsychotic therapy. an inhibiting action of antidepressants on PGE2 would be expected. this finding is consistent with other descriptions of type-1 activation during antipsychotic treatment.18 An increase of “memory cells” (CD4+CD45RO+) cells— one of the main sources of IFN-γ production—during antipsychotic therapy with neuroleptics was observed by different groups. 3 .56 The reduced sICAM-1 levels show a significant increase during short-term antipsychotic therapy. while sertraline and clomipramine additionally raised the IL-10 production. There is significant evidence suggesting that antidepressants of different classes induce downregulation of the type 1 cytokine production in vitro. other groups did not find any effect of some antidepressants on serum levels of different cytokines. predominantly inhibitory effect of selective serotonin reuptake inhibitors (SSRIs) on activation of proinflammatory immune parameters was demonstrated in animal experiments.Neuroimmune dysregulation in psychiatric disorders .61. ref 67) but methodological issues have to be taken into account.74 A recent invitro study showed that both tricyclic antidepressants and selective serotonin inhibitors attenuated cytokine-induced PGE2 and nitric oxide production by inflammatory cells.Vol 11 .70 A decrease of IL-6 serum levels during therapy with different antidepressants has been observed by other researchers.60 Since IL-18 plays a pivotal role in the type-1 immune response.Müller et al Dialogues in Clinical Neuroscience . IL-2 bearing T-cells—during antipsychotic treatment was described. 323 .19.66 There are also studies.71 The shift of imbalanced IFNγ/IL-4 towards normal after 6 weeks' antidepressant treatment has also been reported. type-1 dominated immune state described in MD may be a kind of model state state restricted to a majority of patients suffering from MD. The predominant proinflammatory. in treatment responders. and sIL-2R was found after antidepressant treatment compared with pretreatment values.41 On the other hand. these and other methodological concerns have to be considered carefully in future studies. a significantly reduced production of IFN-γ.61 These findings provide further evidence that antipsychotics have a “balancing” effect on cytokines. IL-2. the TNF-α production decreased to normal. These drugs reduced the IFN-γ production significantly.69 Several researchers have observed a reduction of IL-6 during treatment with the serotonin reuptake inhibitor fluoxetine. Therefore.75 Therapeutic mechanisms and the type-1/ type-2 imbalance in schizophrenia and depression Schizophrenia: antipsychotic drugs correct the type-1/type-2 imbalance In-vitro studies show that the blunted IFN-γ production becomes normalized after therapy with neuroleptics.67 including noradrenaline reuptake inhibitors68 and the “dual” serotonin and noradrenalin reuptake inhibitors.61 Regarding other in-vitro studies.54 These data show that possible different immune states within the category of MD need to be better differentiated. 72 Since IL-6 stimulates PGE2 and antidepressants inhibit IL6 production. No. 2009 hypothesized that high IL-2 levels are associated with suicidality. too. several studies point out that antipsychotic therapy is accompanied by a functional decrease of the IL-6 system. clomipramine.59 An elevation of IL-18 serum levels was described in medicated schizophrenics.

on the other hand. such as IFN-γ and IL-2. probably restricted to astrocytes. Both 3-hydroxykynurenine (3OH-kynurenine) and QUIN can induce neurodegeneration and apoptosis through induction of excitotoxicity and generation of neurotoxic radicals. in contrast. was shown to be overexpressed in postmortem brains of schizophrenic patients.79 The production of KYN metabolites is partly regulated by IDO and tryptophan 2.82 However. ferent types of CNS cells. however. stimulate the activity of IDO. the degradation from tryptophan to kynurenine. sleep deprivation may exert therapeutic effects through a low suppression of type-1 cytokines. Both enzymes catalyze the first step in the pathway. is an NMDA receptor agonist.3-dioxygenase (TDO).78 KYNA acts both as a blocker of the glycine coagonistic site of the NMDA receptor and as a noncompetitive inhibitor of the α7 nicotinic acetylcholine receptor. Type-1 cytokines.3-dioxygenase (IDO).82 The type-2 or Th-2 shift in schizophrenia may result in a downregulation of IDO through the inhibiting effect of Th2 cytokines. that TDO is also expressed in CNS cells. in astrocytes. Thus.Pharmacological aspects Nonpharmacological therapies: electroconvulsive therapy and sleep deprivation Electroconvulsive therapy (ECT) was found to downregulate increased levels of the proinflammatory cytokine TNF-α in patients with MD.77 In contrary. While the excitatory KYN metabolites 3-hydroxykynurenine (3HK) and QUIN are synthesized from KYN in the process toward NAD formation. Antidepressant pharmacotherapy. KAT) has neuroprotective properties through antagonism at the N-methyl-Daspartate (NMDA) receptor. Metabolism of tryptophan via the kynurenine pathway leads to several neuroactive intermediates: kynurenic acid (synthesised by kynurenine aminotransferase. indoleamine 2. Dimitrov. a study referring to the expression of IDO and TDO in schizophrenia showed exactly the expected results. TDO was thought for many years to be restricted to liver tissue. KYNA is one of the several neuroactive intermediate products of the kynurenine pathway (Figure 1). but also other antidepressant therapeutic agents or techniques. Quinolinic acid (QUIN).82 The type-1/type-2 imbalance with type-2 shift is therefore associated with overexpression of TDO. respectively. Kynurenine (KYN) is the primary major degradation product of tryptophan (TRP). TDO. Lange and S. Activity of the key enzyme of the kynurenine pathway. KYNA is formed in a dead-end side arm of the pathway. (blue arrows = activation. not in microglial cells. The type 1/type 2 imbalance is associated with the activation of astrocytes and an imbalance in the activation of astrocytes/microglial cells. It is known today. red arrows = inhibition). and of the 3-OH-kynurenine forming enzyme kynurenine monoxygenase (KMO) is induced by proinflammatory cytokines like interferon-γ (IFN-γ) and inhibited by anti-inflammatory cytokines like interleukin-4 (IL-4).83 The functional excess of astrocytes may lead to a further accumulation of KYNA. but the indole ring of serotonin can also be cleaved by IDO. as expected.76 An immune analysis during sleep showed an increase in the type-1 monocyte derived cytokines TNF-α and IL12 and a decrease of the type-2 IL-10 producing monocytes. continuous wakefulness blocked the increase of type-1 and decrease of type-2 cytokines (T. Neuroimmune interactions of kynurenine intermediates. Indeed. resulting in a coordinate shift in the site (and cell types) of tryptophan degradation. it is necessary to note that the above proposed Neuroprotection Divergent effects of type-1 type-2 immune activation are associated with different effects on the kynurenine metabolism in schizophrenia and depression Schizophrenia The only known naturally occurring NMDA receptor antagonist in the human CNS is kynurenic acid (KYNA). have a downregulating effect on proinflammatory cytokines. 324 . personal communication).80 There is a mutual inhibitory effect of TDO and IDO: a decrease in TDO activity occurs concomitantly with IDO induction. An increased expression of TDO compared with IDO was observed in schizophrenic patients and the increased TDO expression was found.81 While it has been known for a long time that IDO is expressed in dif- IFN-γ IL-4 IDO Kynurenine KMO 3-OH-Kynurenine Tryptophan Kynurenine acid = NMDA-R antagonist KAT Serotonin IFN-γ IL-4 IDO Neurotoxic radicals Quinolinic acid = NMDA-R agonist Neurodegeneration + apoptosis Figure 1. Serotonin is normally degraded to 5-hydroxyindoleacetic acid (5-HIAA).

93 This gives further indirect evidence for a possible link between the type-1 cytokine IFN-γ and the IDO-related reduction of serotonin availability in the CNS of suicidal patients.92. although it has to be taken into consideration that the production of cytokines by astrocytes and microglial cells depends on activation conditions.85 It induces a halt in the lymphocyte cell cycle due to the catabolism of tryptophan. The role of QUIN in depression is discussed in more detail below. since the activity of the enzyme kynurenine 3 mono-oxygenase (KMO). and a decrease in serum concentrations of tryptophan and serotonin on the other hand.96 Therefore. which reflects the activity of IDO. The hypothesis of an overactivation of astrocytes in schizophrenia is supported by the finding of increased CSF levels of S100B— 325 . the type-1/type-2 imbalance in the CNS seems to be represented by the imbalance in the activation of microglial cells and astrocytes. The further metabolism of kynurenine. an increase in monoamino-oxidase (MAO) activity. are involved in depression. directing the production of QUIN. Changes in depressive symptoms were significantly positively correlated with kynurenine and negatively correlated with serotonin concentrations. leading to an increased kynurenine production and a depletion of tryptophan and serotonin. other neurotransmitter systems. increased. 2009 mechanism would fit only for the subpopulation of schizophrenic patients with Th2 dominant immune response. induce synergistically with IFN-γ the increase of IDO activity. Two depressiogenic components result from the IDO activation. not only IFN-γ and type-1 cytokines. which leads to decreased noradrenergic neurotransmission. and the regulation of the tryptophan metabolism. ref 39). Astrocytes.89 Therefore. too. IDO-mediated decrease of CNS tryptophan availability may lead to a serotonergic deficiency in the CNS. is inhibited by type-2 cytokines but activated by proinflammatory type-1 cytokines.94 This study and others95 clearly show that the IDO activity is increased by IFN. Microglial cells.88 An IFN-γinduced. Since increased levels of PGE2 and TNF-α were described in MD. and type-1/type-2 response The cellular sources for the immune response in the CNS are astrocytes and microglia cells. Other proinflammatory molecules such as PGE2 or TNF-α. In addition to the effects of the proinflammatory immune response on the serotonin metabolism. IDO and kynurenine monoxygenase (KMO). deriving from peripheral macrophages. the metabolite of serotonin. but also other proinflammatory molecules induce IDO activity. An imbalance between the NMDA antagonist action by KYNA and the NMDA agonist action by QUIN has been proposed to be involved in the pathophysiology of MD90. including monocytes and microglial cells. The activity of IDO is an important regulatory component in the control of lymphocyte proliferation. (eg. since tryptophan availability is the limiting step in serotonin synthesis. while astrocytes inhibit the production of IL-12 and ICAM-1 and secrete the type-2 cytokine IL-10.87 In contrast to the type-1 cytokines.91 an increased production of QUIN in depressive states would be expected.Vol 11 . however. In those schizophrenics with Th1 dominant immune response. the kynurenine pathway changes would be more similar to those changes in MD. 85 Major depression Two directing enzymes of the kynurenine metabolism. secrete preferantially type-1 cytokines such as IL-12. A study in patients suffering from hepatitis C showed that immunotherapy with IFN-γ was followed by an increase of depressive symptoms and serum kynurenine concentrations on the one hand.3 Accordingly. a recent study demonstrated this imbalance in patients with MD. in CSF are prone to commit suicide. the type-2 cytokines IL-4 and IL-10 inhibit the IFN-γ-induced IDO-mediated tryptophan catabolism. however.87 IDO is located in several cell types. 3 . are induced by the type-1 cytokine IFN-γ. microglia. No.45 The proinflammatory immune state in MD leads on the one hand to a lack of serotonin and on the other hand to an overproduction of the neurotoxic and depressiogenic metabolite QUIN by induction of the directing enzymes of the kynurenine metabolism. Although the relationship of immune activation and changes in catecholaminergic neurotransmission has not been well studied. might be an indirect effect of the increased production of kynurenine and QUIN.Müller et al Dialogues in Clinical Neuroscience .94 The kynurenine/tryptophan ratio.84. seems to play an additional crucial role for the psychopathological states.Neuroimmune dysregulation in psychiatric disorders . in particular the catecholaminergic system. the activation of the type-1 immune response. One of the more consistent findings is that patients with low 5-hydroxyindoleacetic acid (5-HIAA). other proinflammatory molecules also contribute to IDO activation and tryptophan consumption.

the low levels of sICAM-1 (ICAM-1 is the molecule that mainly mediates the penetration of monocytes and lymphocytes into the CNS) in the serum and in the CSF of nonmedicated schizophrenic patients. but they are able to produce large amounts of early kynurenine metabolites. increased glutamatergic activity has been observed in patients with depression. Local CNS concentrations of QUIN are able to exceed the blood levels by far. under certain conditions also leads to increased CNS concentration of QUIN.103 A reduction of astrocytes has also been observed in the dentate gyrus of an animal model of IFN-α induced depression (Myint et al. however. the QUIN production in the CNS might increase without changes of the peripheral blood levels of QUIN. only a small amount of QUIN is produced in astrocytes via a side-arm of the kynurenine metabolism. show that astrocytes are diminished in patients suffering from depression.110 The complete metabolism of kynurenine to QUIN is observed mainly in microglial cells. such as KYN and KYNA. personal communication).113 In the CNS. Recent studies. such as in the limbic and prefrontal cortex.109 However. Therefore.109 Accordingly.106 Neuroprotective and neurotoxic metabolites of the tryptophan-kynurenine metabolism in psychiatric disorders In contrast to microglial cells which produce QUIN. due to the lack of kynurenine-hydroxylase (KYN-OHse). The local QUIN production correlates with the level of β2 microglobulin.Pharmacological aspects a marker of astrocyte activation—independent of the medication state of the schizophrenic patients.102 A loss of astrocytes was in particular observed in younger depressed patients: the lack of glial fibrillary acid protein (GFAP)-immunoreactive astrocytes reflects a lowered activity of responsiveness in those cells. Glial reductions were consistently found in brain circuits known to be involved in mood disorders. They help astrocytes in the further metabolism to QUIN.114 326 . invaded macrophages and microglial cells are able to produce QUIN. a dominance of microglial activation compared with astrocyte activation should be observed in depression. Since the type-1 activation predominates in the response of the peripheral immune system in depression. only macrophage-derived cells are able to convert tryptophan into quinolinic acidolonic acid. not in subcortical areas. but also in astrocytes. it has been pointed out that astrocytes cannot produce the product 3-hydroxykynurenine (3-HK).99. however. in a model of infection. A second key player in the metabolization of 3-HK are monocytic cells infiltrating the CNS.57 Quinolinic acid as a depressiogenic and neurotoxic substance Apart from certain liver cells.112 Peripheral immune stimulation.111 A recent study showed that depressive symptoms are related to an high ratio of KYN/KYNA in depression.22 and the increase of adhesion molecules during antipsychotic therapy indicate that the penetration of monocytes may be reduced in nonmedicated schizophrenic patients. KYNA may accumulate in astrocytes.98 A type-1 immune activation as an effect of antipsychotic treatment has repeatedly been observed.107 The cellular localization of the kynurenine metabolism is primarily in macrophages and microglial cells. in case of high tryptophan breakdown to KYN. an inflammatory marker.109 This supports the observation that inhibition of KMO leads to an increase in the KYNA production in the CNS. this difference is crucial due to the different effects of the type-1/type-2 immune response.111 During a local inflammatory CNS process. a critical enzyme in the kynurenine metabolism. This finding points out that high levels of QUIN therefore may be associated with cortical dysfunction.104 Impaired glutamate reuptake from the synaptic cleft by astroglia prolongs synaptic activation by glutamate. is absent in human astrocytes.108 KMO. however. astrocytes play a key role in the production of KYNA in the CNS.105 Accordingly. Astrocytes are the main source of KYNA. 100 Although several authors did not differentiate between microglial and astrocytic loss. Moreover.112 The strong association between cortical QUIN concentrations and local IDO activity supports the view that the induction of IDO is an important event in initiating the increase of QUIN production.101 although the data are not entirely consistent.101 A loss of astrocytes was found in many cortical layers and in different sections of the dorsolateral prefrontal cortex in depression. a loss of astrocytes is associated with an impaired reuptake of glutamate from the extracellular space into astrocytes by high affinity glutamate transporters. the highest concentrations of QUIN are found in the gray and white matter of the cortex.111 Interestingly.97 Microglia activation was found in a small percentage of schizophrenics and is speculated to be a medication effect.

COX-2 inhibitors influence the CNS serotonergic system. COX-2 inhibition as a therapeutic approach in schizophrenia and depression COX inhibition provokes differential effects on kynurenine metabolism: while COX-1 inhibition increases the levels of KYNA. COX-2 inhibitors seem to show advantageous results: animal studies show that COX-2 inhibition can lower the increase of the proinflammatory cytokines IL-1β. while the KYNA pathway is neglected.116 QUIN was shown to cause an over-release of glutamate in the striatum and in the cortex. a therapeutic effect of celecoxib was observed. In a rat model. however. similar positive results of cyclo-oxygenase inhibition were able to be obtained: in a Chinese population of first-manifestation schizophrenics. ie. 2009 The increase of this ratio reflects that in depressed states KYN may be preferentially metabolized to QUIN. but it can also prevent clinical symptoms such as anxiety and cognitive decline. possibly in part due to methodological concerns.117 The QUIN pathway of the kynurenine metabolism—directed by proinflammatory cytokines—might be the key mechanism involved in the increased glutamatergic neurotransmission in MD. The data are still preliminary and further research has to be performed.112 In an animal model. Thus. COX-2 inhibition decreases them. Moreover.120 The finding of a clinical advantage of COX-2 inhibition. TNF-α. randomized.118 Therefore. however. 3 . treatment with the COX-2 inhibitor celecoxib—but not with a COX-1 inhibitor—prevented the dysregulation of the HPA-axis.122.118 Indeed. with other COX-2 inhibitors. which are associated with this increase of proinflammatory cytokines. 119 Immunologically. an excess of QUIN might be associated with excess glutamatergic activation. an increase of QUIN and 3-hydroxykynurenine was associated with anxiety.128 Additionally. were assigned to the COX-1 mediated increase of KYNA. The increase of QUIN was observed to be associated with several prominent features of depression: decrease in reaction time115 and cognitive deficits. 126 This effect can be expected because PGE2 stimulates the HPA axis in the CNS. in particular the increase of cortisol. No. COX-2 inhibition showed beneficial effects preferentially in early stages of the disease. and of PGE2. in a prospective.130 In the depression model 327 . The reduction of KYNA levels.127 and PGE2 is inhibited by COX2 inhibition.123 and in an Iranian sample of chronic schizophrenics. from neurotoxicity.122 In subsequent clinical studies following a similar randomized double-blind placebo-controlled add-on design of 400 mg celecoxib to risperidone (in one study risperidone or olanzapine) in partly different patient populations.121 This observation is in accordance with results from animal studies showing that the effects of COX-2 inhibition on cytokines.122 Moreover. In particular. eg. double-blind study of therapy with the COX-2 inhibitor celecoxib added on to risperidone in acute exacerbation of schizophrenia. COX-2 inhibition as a possible anti-inflammatory therapeutic approach in depression Due to the increase of proinflammatory cytokines and PGE2 in depressed patients. COX-2 inhibitors also protect the CNS from effects of QUIN. and particularly on behavioral symptoms are dependent on the duration of the preceding changes and the time point of application of the COX-2 inhibitor. Moreover. in particular difficulties in learning. the functional effects of IL-1 in the CNS—sickness behavior being one of these effects— were also shown to be antagonized by treatment with a selective COX-2 inhibitor. Further analysis of the data revealed that the outcome depends on the duration of the disease. presumably by presynaptic mechanisms. observed during therapy with COX-1 inhibitors. anti-inflammatory treatment would be expected to show antidepressant effects also in depressed patients. by a prostaglandin-mediated mechanism.129 A possible mechanism of the antidepressant action of COX-2 inhibitors is the inhibition of the release of IL-1 and IL-6. psychotic symptoms and cognitive dysfunctions. could not be replicated in a second study.124 In continuously ill schizophrenics. treatment with rofecoxib was followed by an increase of serotonin in the frontal and the temporoparietal cortex.Vol 11 .Müller et al Dialogues in Clinical Neuroscience .Neuroimmune dysregulation in psychiatric disorders . hormones.125 In schizophrenia. one of the biological key features associated with depression. 106 while it is unclear whether QUIN itself has depressiogenic properties. might be an additional mechanism to the above-described immunological mechanism for therapeutic effects of selective COX-2 inhibitors in schizophrenia. the data regarding chronic schizophrenia are controversial. an increase of the type-1 immune response was found in the celecoxib treatment group. no advantage of celecoxib could be found.

7. Kincaid K. which might be more related to the pathophysiology of these disorders compared with the neurotransmitter disturbances. Ackenheil M.15:1595-1611. Other anti-inflammatory therapeutic approaches will be of interest in the future. Jones P. 2009. Conclusion A large number of findings point out that inflammation plays a pivotal role in the pathogenesis of major psychiatric disorders. Kynurenine pathway in major depression: evidence of impaired neuroprotection. brain maturation and the risk of psychosis. Steinbusch H.134 Currently. are candidates for antidepressants and antipsychotics.34:1854-1864. the mixed COX1/COX-2 inhibitor acetylsalicylic acid showed an additional antidepressant effect by accelerating the antidepressant effect of fluoxetine. Mol Psychiatry. Machado-Vieira R. Foccacia R. a large study with the COX-2 inhibitor cimicoxib is ongoing. 328 . the mixed COX-1/COX2 inhibitor acetylsalicylic acid accelerated the antidepressant effect of fluoxetine and increased the response rate in depressed nonresponders to monotherapy with fluoxetine in a open-label pilot study. Arch Gen Psychiatry. Scharpe S. generates neurotoxic and neuroprotective metabolites. van Bergeijk DP. 15. Allebeck P. double-blind pilot add-on study using the selective COX-2 inhibitor celecoxib in MD. The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. The effects of memantine on prepulse inhibition. 2000. however. and dopaminergic neurotransmissions. Bergsma F. 2005. 2007. Psychoneuroendocrinology. Neurol Psychiatry Brain Res. Swerdlow NR. The neurotransmitter disturbances might be a final common pathway of different pathological pathways in schizophrenia and depression. Hampel HJ. Anti-inflammatory drugs. Kraus T.254:2326. 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Sperner-Unterweger B. 2009 El impacto de la falta de regulación neuroinmune sobre la neuroprotección y la neurotoxicidad en los trastornos psiquiátricos: su relación con tratamientos farmacológicos Se ha postulado una patogénesis inflamatoria para la esquizofrenia y la depresión mayor (DM). 2000. Ackenheil M. En ce qui concerne la fonction neuroprotectrice de l’acide kynurétique et les effets neurotoxiques de l’acide quinolinique (QUIN). 2001. montrant des effets favorables dans la schizophrénie et la dépression. 329 . Schuld A. Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. ed. Sin embargo. Widner B. los efectos inmunológicos de muchos de los antipsicóticos y antidepresivos existentes corrigen parcialmente el desequilibrio inmune y el exceso de producción del neurotóxico QUIN. la production d’acide kynurétique étant augmentée dans la schizophrénie et diminuée dans la dépression. Austria. différents schémas d’activation immunitaire peuvent aussi conduire à un déséquilibre entre les effets neuroprotecteurs et neurotoxiques du métabolisme tryptophane/kynurénine. Fuchs D. 3 . Eur Arch Psychiatry Clin Neurosci. el cual puede contribuir a una excesiva acción agonista del N-metil-D-aspartato (NMDA) en la depresión y otra antagonista del NMDA en la esquizofrenia. Respecto a la función neuroprotectora del ácido kinurénico y a los efectos neurotóxicos del ácido quinolínico (QUIN). 1999. Miller C. Holzner B. Cytokine-associated emotional and cognitive disturbances in humans. Riedel M. auquel peut contribuer l’activation différentielle des cellules de la microglie et des astrocytes. 1996. Le déséquilibre immunologique provoque un état inflammatoire associé à une production augmentée de prostaglandine E2 et à une expression augmentée de la COX-2 (cyclooxygénase-2).Vol 11 . y orientan a efectos favorables en la esquizofrenia y en la DM.246:279-284. Müller N. Fleischhacker WW. Ces différences sont associées à un déséquilibre de la neurotransmission glutamatergique qui peut entraîner une action agoniste excessive du NMDA (N-méthyl-Daspartate) dans la dépression et à une action antagoniste dans la schizophrénie.relation avec le traitement médicamenteux L’hypothèse d’une pathogenèse inflammatoire a été avancée pour la schizophrénie et la dépression majeure (DM). Vienna. Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients. Reichenberg A. Psychoimmunology.3 dioxigenasa y en el metabolismo triptófano-kinurenina.Neuroimmune dysregulation in psychiatric disorders . Measurement of neopterin. Arch Gen Psychiatry. Arolt V. :115-119. 19. and Viruses. NY: Springer. In: Müller N. Los inhibidores de la COX-2 se han evaluado en modelos animales de depresión y en ensayos clínicos preliminares. Kirchner H. Yirmiya R. kynurenine and tryptophan in sera of schizophrenic patients. 17. Wilke I. Les inhibiteurs de la COX-2 ont été testés dans des modèles animaux de dépression et dans des études cliniques préliminaires.3dioxygénase et dans le métabolisme tryptophanekynurénine. World J Biol Psychiatry. Weitzsch C. Psychiatry.58:445-452. El desequilibrio inmunológico se traduce en un estado inflamatorio combinado con un aumento de la producción de prostaglandina E2 y aumento de la expresión de ciclo-oxigenasa-2 (COX2).1:173-179. En la esquizofrenia y la depresión. Dans la schizophrénie et la dépression. patrones opuestos de respuesta inmune tipo 1 versus tipo 2 parecen estar asociados con diferencias en la activación de la enzima indolamina 2. Les effets immunologiques de nombreux antipsychotiques et antidépresseurs existants corrigent cependant en partie ce déséquilibre immunitaire et l’excès de production du neurotoxique QUIN. Impact d’une dysrégulation neuro-immune sur la neuroprotection et la neurotoxicité dans les troubles psychiatriques. et al. New York. Hornberg M. l’opposition des réponses immunes de type 1 vs type 2 semble être associée à des différences dans l’activation de l’enzyme indoleamine 2. Rothermundt M.Müller et al Dialogues in Clinical Neuroscience . Estas diferencias están asociadas con un desequilibrio en la neurotransmisión glutamatérgica. La activación diferencial de las células de la microglía y los astrocitos puede ser un mecanismo adicional que contribuya a este desequilibrio. Schwarz MJ. No. lo que lleva a un aumento de la producción de ácido kinurénico en la esquizofrenia y disminución de la producción de este ácido en la depresión. 20. los diferentes patrones de activación inmune también pueden llevar a un desequilibrio entre los efectos neuroprotectores y neurotóxicos del metabolismo triptófano/kinurenina. 18.

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MA. Daniel R. These agents also upregulate the expression of trophic/protective molecules such as brain-derived neurotrophic factor.11:333-348. PI3-kinase. and regeneration. 2009. serine-threonine kinase. 1C-912. NIMH. antipsychotic. Bethesda. but also neurodegenerative diseases and ischemia. if not all. antidepressant. we review evidence from animal and human studies reporting that psychotropic agents affect molecular targets and signaling cascades associated with enhanced Keywords: mood stabilizer. Copyright © 2009 LLS SAS. nerve growth factor. psychiatric disorders such as mood disorders and schizophrenia have been conceptualized as neurochemical illnesses. whereas neuroprotective effects slow or halt the progression of neuronal atrophy or cell death following the onset of disease or clinical decline. volumetric reduction. They also promote neurogenesis and are protective in models of neurodegenerative diseases and ischemia. LLS SAS istorically. Most. These psychotropic agents include mood stabilizers.Pharmacological aspects The neurotrophic and neuroprotective effects of psychotropic agents Joshua Hunsberger. Henter. Bethesda. Furthermore. NIMH. Several psychotropic agents— defined as chemical substances that act primarily on the central nervous system (CNS) to alter brain function— are used to treat psychiatric disorders.gov) H Dialogues Clin Neurosci. PI3-kinase signaling. neuroprotection. accumulating data from both postmortem and brain imaging studies reveal morphological changes in the brains of individuals with these illnesses. growth. MD 20892. Mood and Anxiety Disorders Program. antidepressants. PhD. Wnt/GSK-3 signaling Author affiliations: Laboratory of Molecular Pathophysiology and Experimental Therapeutics. 35 Convent Drive. and Bcl-2 associated athanogene 1. differentiation. Taken together. and inactivate proapoptotic molecules such as GSK-3. PhD. Many of these drugs exert significant effects on signaling pathways enhancing neurotrophic and neuroprotective cellular mechanisms. and antipsychotics realize their neurotrophic/neuroprotective effects by activating the mitogen activated protein kinase/extracellular signal-related kinase. Guang Chen. and antipsychotic medications.nih. These changes include ventricle enlargement. MD. In this article.org . Mood and Anxiety Disorders Program. Ioline D. attenuation of neuronal viability marker N-acetyl aspartate (NAA). Bldg 35. and atrophy or loss of neurons and glial cells in selective cortical and limbic brain regions. antidepressants. NIH. © 2009. ERK signaling. as well as levels of N-acetyl aspartate and glutamate in selected brain regions. neurotrophic. Maryland. Loosely defined. human imaging studies have found that these agents increase the volume and density of brain tissue. and wingless/glycogen synthase kinase (GSK) 3 signaling pathways. All rights reserved 333 www. B-cell lymphoma 2. these data suggest that the neurotrophic/neuroprotective effects of these agents have broad therapeutic potential in the treatment. BA.dialogues-cns. Austin. However. USA Address for correspondence: Guang Chen MD. not only of mood disorders and schizophrenia. neurogenesis. USA (e-mail: guangchen@mail. PhD Accumulating evidence suggests that psychotropic agents such as mood stabilizers. neurotrophic effects can be considered a therapeutic strategy intended to augment proliferation. of this evidence was collected from animal studies that used clinically relevant treatment regimens.

GTP bond RAS. The targets of ERK include protein kinases such as RSK and MNK. Indeed. ion channel. and racing thoughts) and depression (characterized by low mood. anhedonia. increased energy. an ERK-regulated transcription factor. these data indicate that valproate activates the ERK pathway and produces neurotrophic-like cellular effects through this activation.12 hippocampal progenitor cells. and long-term synaptic remodeling and plasticity. our incomplete understanding of the pathophysiology of BPD. These therapeutic agents do not simply target a particular neurotransmitter system or cellular signaling cascade. and ii) the wingless/glycogen synthase kinase 3 (Wnt/GSK3) pathway.10 Valproate also promoted neurite outgrowth and expression of GAP-43 in these cells. Follow-up studies showed that in cultured cerebral cortical cells. neurotransmitters. and that activation was blocked by a MEK inhibitor. ii) the phosphatidylinositol 3 kinase (PI3K) pathway.10 Taken together. but diverse targets implicated in many signaling pathways.Pharmacological aspects Selected abbreviations and acronyms BDNF CREB ERK MAPK NAA P13K Wnt/GSK brain-derived neurotrophic factor cAMP response element binding extracellular signal-related kinase mitogen activated protein kinase N-acetyl aspartate PI3-kinase wingless/glycogen synthase kinase (MAPK/ERK) pathway. Mood stabilizers activate neurotrophic signaling pathways Mood stabilizers have been reported to activate the intracellular MAPK/ERK signaling pathway (Figure 1). Mood stabilizers Mood stabilizers are used to treat bipolar disorder (BPD). in which both genetic and environmental predispositions may impair cellular resilience and lead to dysfunctional circuits and synapses. a small G protein. and MAPK/ERK. MEK. the mood stabilizers carbamazepine and valproate—both used to treat the manic symptoms of BPD—have anticonvulsant properties and were developed for the treatment of epilepsy. RAF then phosphorylates and activates MEK. that activation was further blocked by RAS and RAF functional null mutant.3 Valproate-induced activation of the ERK pathway has also been identified in primary cortical neurons. induces RAF activity. In SH-SY5Y human neuroblastoma cells.11 cerebral progenitor cells.13 and endothe- neurotrophic and neuroprotective mechanisms.1-3 This pathway is used by neurotrophins. which in turn phosphorylates and activates MAPK/ERK. impaired judgment. the mood stabilizers lithium and valproate activated AP-1 transcription factors. This may be because mood stabilizers were often designed to treat different disorders. and transcription factors.10 That study also demonstrated that valproate increased levels of activated phospho-ERK and reporter gene expression driven by ELK. neuronal survival. RSK and MNK are thought to phosphorylate and activate transcription factor cAMP response element binding (CREB). we will also review the available evidence that antidepressants and antipsychotics exert similar neurotrophic effects. as well as reverse or reduce behavioral deficits associated with preclinical animal models of mania and depression and other psychiatric illnesses.8 and brain-derived neurotrophic factor (BDNF) 9 to enhance neuroprotection and neuronal survival mechanisms. While much of this work has focused on the mood stabilizers lithium and valproate. further supports the notion that these agents affect diverse targets. and neuropeptides to exert their neurotrophic and neuroprotective effects by specifically enhancing progenitor cell proliferation and differentiation. Below we focus on several intracellular signaling pathways targeted by mood stabilizers that may underlie these therapeutic mechanisms: i) the mitogen activated protein kinase/extracellular signal-related kinase 334 . etc). neurotransmitter receptors. which could be blocked by an ERK pathway inhibitor. valproate induced ERK pathway activation in a manner that was more sustainable than activation by growth factors.4-7 The key components of the pathway are three serine/threonine-selective kinases: RAF. notably. In addition. however. mood stabilizers may achieve their therapeutic effects by working through these diverse targets to restore cellular resilience. including B-cell lymphoma 2 (Bcl-2)1. neuronal process growth and regeneration. CREB regulates the expression of many different genes. which is characterized by mood shifts between mania (characterized by elevated mood. for instance. and their use in the treatment of BPD frequently arose through serendipity. chronic treatment is necessary for their neurotrophic and neuroprotective actions to improve functional plasticity in cortical and limbic circuits and synapses.

PDK. RNA polymerase II.14 Lithium similarly increased activation-phosphorylation of ERK in SY5Y cells. serine/threonine protein kinase AKT.17 hippocampal progenitor cells. PI3K. lamotrigine still showed neuroprotective effects in models of ischemia and kainate (KA)-induced neurotoxicity. MEK or Map2k1. The MAPK/ERK. extracellular regulated kinase.22 Another study found that valproate increased levels of activated phospho-ERK and activated phospho-CREB in mice with intracerebral hemorrhage. B-cell lymphoma 2. phosphatidylinositol 3 kinase.21 Taken together. BDNF A CR EB CR EB . CREB binding protein. brain-derived neurotrophic factor. histone acetyltransferase. Wnt. Akt. lamotrigine. resistance to audiogenic seizures. TrkB. however. APP-AB. Ras. antidepressants. amyloid beta (A4) precursor protein. GSK-3. Targets reported to be regulated by antidepressants. CBP. In a series of in vivo studies. or multiple types of treatments (orange) are highlighted. 2009 lial cells. RAF proto-oncogene serine/threonine-protein kinase.Hunsberger et al Dialogues in Clinical Neuroscience .Vol 11 . RNA POLII. quiescent astrocytes.20. No. RSK. BDNF.Beneficial effects of psychotropic agents . perhaps through glutamate release inhibition. wingless 335 H D A Bcl-2. CREB.19 and primary cortical neurons. and Wnt/GSK3 signaling cascades. HAT. circles indicate inhibition. Bcl-2 associated athanogene. antipsychotics. BAG-1. mitogen-activated protein kinase kinase 1. Arrowheads indicate activation. Intracellular signaling pathways targeted by psychotropic agents. ribosomal protein S6 kinase. and antipsychotics target these signaling cascades.2. Bcl-2.17 Furthermore. HDAC. ERK. glycogen synthase kinase 3.16.11 Lithium inhibited the ERK pathway in cultures of serum-deprived.23 Another study found that Wnt Frizzled TrkB TrkB P13K Ras PDK Dishevelled Secretase Raf AKT GSK3 APP-Aβ MEK BA G 1 Tau ERK Mitochondria Bc l-2 Nucleus T C RSK H CBP RNA POLII Figure 1. type 2. mood stabilizers (red). and activated phospho-CREB in prefrontal cortex and hippocampus. Molecules in blue are critical constituents of the selected pathways that have not been found to be affected by any of the treatments discussed in this review. Psychotropic agents such as mood stabilizers. 90kDa. cAMP response element binding.18.3 Lithium-induced increases in activated phospho-ERKs were also observed in the caudate/putamen of infant mouse brains. an anticonvulsant prescribed to prevent recurrences of depression or mania in BPD. did not affect the ERK pathway in SH-SY5Y cells15 or primary cortical neurons11. histone deacetylase. 3 . Raf. these in vitro data suggest that actiBDNF vation of the ERK pathway is common to only a subgroup of mood stabilizers and is cell-type specific. Chen and colleagues found that chronic treatment with lithium or valproate increased levels of activated phospho-ERK. phosphoRSK1. PI3K. pyruvate dehydrogenase kinase.15 cerebellar granular cells. neurotrophic tyrosine kinase receptor.

glial cell-line derived neurotrophic factor (GDNF). Bcl-2 and its family proteins are the major modulators of apoptosis. and reduced phosphoERK levels in the amygdala.18.2. Mood stabilizers target several of these major components of the PI3K pathway. for instance. lithium increased serum BDNF levels in patients with Alzheimer’s disease.32. neurotrophin 3 (NT-3).6. similar effects were noted in human SH-SY5Y cells treated with lithium and valproate. PDK.34 as well as in a mouse model of intracerebral hemorrhage.43.1 Mood stabilizers promote neurogenesis and neuronal process growth The discovery that mood stabilizers can regulate growth factors and produce neurotrophin-like molecular effects led investigators to explore whether these agents could augment hippocampal neurogenesis. phospho-GSK-3α and phospho-GSK-3β in the striatum of dopamine transporter knockout (DAT KO) mice within 30 minutes of administration.48-54 This upregulation appears to be partially due to activation of the ERK and PI3K pathways. leading to CREB activation and CRE-mediated gene transcription of BDNF.32. and GSK-3 are thought to be the major components of the PI3K pathway. Mood stabilizers upregulate levels of neurotrophic and neuroprotective molecules Studies show that lithium and valproate increased mRNA and protein levels of neurotrophins such as BDNF.29 Interestingly.55 In vitro evidence showed that lithium induced neuronal differentiation of hippocampal neural progenitor cells via a phospho-ERK and phospho-CREB dependent pathway. the regulatory subunit of PI3K is stimulated by the adapter proteins Grb-2 and Grb-2-associated binding protein 1/2 (Gab1/2). increased levels of activated phospho-Akt as well as phospho-GSK-3. resulting in PI3K activation.33 Valproate increased activated brain phospho-Akt in skeletal muscle in a mouse model of Duchenne’s muscular dystrophy. IP) significantly increased levels of phospho-Akt.40. PKB). PIP3 provides docking sites for phosphoinositide-dependent kinase (PDK) and the serine-threonine kinase Akt (also known as protein kinase B.30-32 Lithium injections (200 mg/kg of body weight.35-46 Furthermore. indicating that they required PI3K activation.5-trisphosphate (PIP3). Notably. Activated PI3K converts plasma membrane lipid phosphatidylinositol-4. numerous studies have shown that chronic treatment with lithium or valproate upregulates Bcl-2 and Bcl-2 associated athanogene (BAG-1) levels in the brain or nerve tissues. Valproate’s inhibition of histone deacetylase (HDAC) via an epigenetic mechanism—a molecular process that leads to gene activation and deactivation—may also play a role. Lithium and valproate were indeed found to promote hippocampal neurogenesis in neuronal cell culture and rodent studies. Acute (minutes to hours) or subacute (several days) lithium treatment of cerebellar granule cells.45 by stimulating the ERK and PI3K pathways using lithium or valproate. These mechanisms may include enhancing BDNF promoter activation40. as well as increased transcriptional activity of CREB.56 Valproate activated the ERK pathway and promoted differentiation of hippocampal 336 . leads to the inactivation of this enzyme. and that an ERK pathway inhibitor blocked lithium’s survival effects.43.29 Chronic lithium and valproate treatment also increased levels of phospho-GSK-3β in mouse cerebral cortex and hippocampus.19.3.4.23 These data demonstrate that lithium and valproate stimulate the PI3K pathway in vivo and subsequently inactivate GSK-3. Simultaneous binding of PDK and Akt at the PI3K activation site facilitates phosphorylation of Akt by PDK1 and enhances Akt activity. a product of Akt-catalyzed phosphorylation.47 The effects of mood stabilizers on BDNF levels are thought to be mediated via several different mechanisms. Akt.23.5-biphosphate (PIP2) to phosphatidylinositol-3.28 PI3K. which in contrast to most phosphorylations.30 The increases were blocked by PI3K inhibitors. mood stabilizers also target neuroprotective molecules such as Bcl-2. The catalytic subunit of PI3K is also stimulated by direct interaction with activated RAS.24 suggesting that mood stabilizer-induced ERK pathway activation/inactivation may be brain region-specific.Pharmacological aspects valproate did not induce changes in phospho-ERK levels in the nucleus accumbens.25-27 Upon trophic factor stimulation (Figure 1).1. Akt then phosphorylates glycogen synthase kinase-3 (GSK-3). The phosphatidylinositol 3 kinase (PI3K) pathway—a regulator of neuronal survival and plasticity—is also regulated by growth factors (Figure 1). and vascular endothelial growth factor (VEGF) in cultured cells and brain regions.45 In addition to targeting neurotrophic mechanisms.19 An in vivo study showed that lithium increased survival of newborn cells in hippocampus.

is the only FDAapproved treatment for this disease.51. 91 Valproate was similarly found to increase hippocampal NAA levels. Riluzole.3. Another recent study showed that lithium facilitated motor function recovery and axonal regeneration after spinal cord injury. valproate’s differentiation effects were thought to be mediated through HDAC inhibition. Interestingly. especially in unmedicated patients with a family history of mood disorders. 79 a finding replicated by other investigators.61 Although the molecular mechanisms of this lithium-induced morphological action are still not fully understood.81 hippocampal volume. and these effects were associated with increased inactivated-phospho-GSK-3.72 Mood stabilizers produce neuroprotective effects in animal models of disease Mood stabilizers are known to protect cultured cells from a variety of insults (for reviews see refs 6. In this section. amyotrophic lateral sclerosis (ALS). neurodegeneration.4 protected retinal ganglion cells following partial optic nerve crush in rats.80 left anterior cingulate volume.10 Animal studies have found that valproate facilitated axonal regeneration and motor function recovery after sciatic nerve axotomy. riluzole itself has been associated with neuroprotective 337 .93). brain imaging studies show brain ventricular enlargements. HIV-associated cognitive impairments. 3 . and spinocerebellar ataxia).79 Similar findings were also obtained in other longitudinal and cross-sectional studies of cerebral grey matter volume.Beneficial effects of psychotropic agents .92. investigators used imaging tools to assess the effects of mood stabilizers on brain morphometric and neurochemical measures. not ERK pathway activation. they are particularly important because social-psychological and behavioral stress cause a variety of brain changes and are key contributing factors to mood disorders. Moore and colleagues found that lithium treatment increased cerebral grey matter volume.7).7. and neuroinflammation (eg.106 ALS is a progressive. No.96-104 Follow-up studies showed that valproate had similar protective effects on ischemia-induced brain infarction. which was blocked by ERK pathway inhibition.67 cortical regional morphometric reductions. Valproate also promoted neurite growth in cultured cells (for reviews see refs 6. thought to be mediated by Bcl-2. however. Lithium treatment initiated 2 weeks before the stress and continued throughout a 3-week period of stress attenuated these stress-induced reductions in apical dendritic lengths. in part. we review the neuroprotective effects of lithium and valproate in a series of models of brain ischemia.58 Lithium similarly enhanced survival and axonal regeneration of cultured retinal ganglion cells. Chuang and colleagues found that ischemic infarct size induced by occlusion of the left middle cerebral artery was markedly reduced by lithium treatment administered before94 or after95 the induction of ischemia.57 Whether valproate uses multiple mechanisms to induce hippocampal neurogenesis in intact animals remains to be elucidated. lethal neurodegenerative disease with no known cure.82-86 and amygdala volume. Alzheimer’s disease (AD). these findings have since been replicated by other investigators. 2009 neural progenitor cells in culture.70 right anterior cingulate volume. In a seminal study using an animal model of ischemia.Vol 11 .53 These neuroprotective findings are. In a magnetic resonance imaging (MRI) study.66.62-65 Evidence from human imaging studies for neurotrophic/neuroprotective actions of mood stabilizers As noted previously. Intrigued by the discovery that Bcl-2 is upregulated by mood stabilizers.59 and promoted axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord.86 A cross-sectional study found that valproate similarly increased left anterior cingulate volume in individuals with BPD.Hunsberger et al Dialogues in Clinical Neuroscience . which prolongs the survival of patients by several months.68-72 and cerebral and hippocampal level reductions of NAA72-78 in individuals with mood disorders. Huntington’s disease.13. Chronic behavioral stress shortens apical dendrites in the CA3 region of the hippocampus in rodents.87 One initial longitudinal MRS study found brain regional increases in NAA levels in individuals with BPD and healthy subjects treated for 4 weeks with lithium.105.88-90 NAA levels were also found to be correlated with brain lithium levels in a study of elderly patients with BPD. cerebral ischemia. Further support for GSK-3’s role in lithium’s neuroprotective effects came from a study where lithium’s effects were mimicked by the GSK-3 inhibitor SB415286.60 Another area where lithium exerts neuroprotective effects is in stress-induced morphological alterations.

Mutations in the genes of presenilins—the core component of γ-secretase.and γ-secretase. which occurs immediately.124 and aluminum-induced neurodegeneration.111 and that chronic lithium treatment reduced Aβ produced in a genetic mouse model of AD. these effects were also associated with increased phospho-GSK-3β. neurofibrillary tangles. including animal models of Huntington’s disease. lithium treatment reduced brain tau phosphorylation and increased brain GSK-3α and β phosphorylation at the inhibitory sites.50. One series of experiments in cultured cells found that GSK-3α increased Aβ production. improved performance in the water maze. reduced neuritic plaque formation.122 Antidepressants Chemical antidepressants used to treat depressive disorders. chronic administration of lithium initiated before or after the deficit onset had a positive effect on multiple behavioral measures and hippocampal neuropathology. lithium treatment reduced Aβ production.122 HIV-induced encephalitis and dementia. a clinical trial found that lithium.114 Neurofibrillary tangles are formed by hyperphosphorylated tau. therapeutic effects are observed only after a few days.50 At least some of these effects are associated with increased Bcl-2 levels.110 both delay disease onset and prolong lifespan in SOD1-G93A mice.gov/ for more information).115 Given these promising preclinical data. Nevertheless. This suggests that adaptive changes in cellular signaling cascades may underlie 338 . Aβ protein is derived from amyloid precursor protein (APP) through an endoproteolytic cleavage catalyzed by β. a microtubule-associated protein. studies began to examine the potential long-term neurotrophic/ neuroprotective effects of lithium and valproate in humans.119 Indeed. While some studies suggest that naturalistic lithium treatment may indeed be associated with neuroprotective effects in individuals with AD (see. however. for instance refs 47. considerably more data are required.109 With regards to AD. and often not until 2 weeks or more. a model for ALS. GSK-3 is a major tau kinase and GSK-3β hyperactivity is known to contribute to tau hyperphosphorylation in cell and animal models.Pharmacological aspects properties. this remains a promising and exciting area for further investigation. all of which are associated with decreased APP phosphorylation and increased levels of phospho-GSK-3β.121.112 In another animal model of AD where APP23 transgenic mice carried human APP751 cDNA with the Swedish double mutation at positions 670/671. tricyclic antidepressants (TCAs). however. lithium and valproate together produce an additive protective effect in SOD1-G93A mice compared with either treatment alone. In a SCA1 mouse model. Interestingly. clinical trials of lithium in patients with SCA1 are currently ongoing (see http://clinicaltrials.120. In a transgenic mouse strain overexpressing mutated (London V717I and Swedish K670M/N671L) human APP (hAPP751). the histological hallmarks of AD include amyloid plaques.107 SOD1-G93A mice. or selective norepinephrine reuptake inhibitors (SNRIs).116-118). for most patients. lithium treatment reduced tau phosphorylation in the brains of mice overexpressing mutated (London V717I and Swedish K670M/N671L) human APP (hAPP751). Qing and colleagues observed that valproate treatment decreased Aβ production. AD is a leading cause of dementia in the aging population and the most common neurodegenerative disease without an effective treatment.112 In another AD model (3xTG-AD). The plaques consist of insoluble deposits of amyloid-beta (Aβ) protein and cellular material outside and around neurons. These mice expressed APPSwedish (Tg2576) and also carried a knock-in mutation of presenilin-1 (PS1P264L). carry a high copy number of this transgene with the G93A human SOD1 mutation. APP.123. selective serotonin reuptake inhibitors (SSRIs). the neuroprotective effects of lithium and valproate have also been reported in additional disease and insult models. and neuronal loss.110 Notably. or depressive symptoms in other psychiatric disorders. diverse studies have suggested that lithium’s neuroprotective effects may have a potential role in the therapeutics of this disease. Finally.120. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction.113. and tau are associated with AD. Studies show that valproate108 and lithium109. include monoamine oxidase inhibitors (MAOIs). and improved memory deficits.121 Parkinson's disease. These chemical antidepressants act by increasing monoamines (serotonin and/or norepinephrine) in the synaptic cleft. compared with riluzole. Briefly. and preserved dendritic structure in the frontal cortex and hippocampus. Furthermore. it did not improve memory or reduce Aβ protection. further delays disease progression and death in individuals with ALS.

a MAOI used to treat both depression and neurodegeneration that has promising neuroprotective effects. tranylcypromine) inhibiting both MAO-A and MAO-B protected against 1-methyl-4-phenyl-1.137 This enhancement in BDNF by antidepressants may help promote mechanisms of neuronal protection and survival key to reducing stress-induced damage. MEK2. nonchemical antidepressants such as electroconvulsive therapy (ECT) and exercise also target these pathways and may employ similar therapeutic mechanisms. fluoxetine’s neuroprotective effects. and ERK2. Antidepressants have also been found to have neuroprotective effects. chronic antidepressant treatment prevented these stress-induced changes. trkB.150 and exercise increased hippocampal neurogenesis151 in addition to enhancing hippocampal-dependent learning and long-term potentiation (LTP). Furthermore. In humans. exercise also possesses neuroprotective effects. Effects of antidepressants on neurogenesis in animals Antidepressants increase hippocampal adult neurogenesis following chronic but not acute treatment. chronic antidepressant treatment also increased the expression of CREB mRNA in the rat hippocampus. both chemical antidepressants and ECT increase BDNF levels. while stress decreases hippocampal neurogenesis. or the SNRI reboxetine produced an approximately 20% to 40% increase in bromodeoxyuridine BrdU-labeled hippocampal cells145. 3 . the MAOI tranylcypromine. In rats.125 Two such pathways that will be considered below include the MAPK/ERK and the Wnt/GSK signaling cascade (Figure 1). For instance. Carro and colleagues showed that rodents subjected to treadmill running were protected against various insults ranging from treatment with the neurotoxin domoic acid to inherited neurodegeneration affecting Purkinje cells of the cerebellum.143 Notably. For instance. in addition to restoring serotonin levels. MDMA).148 as well as hippocampal synapse number. Interestingly.Vol 11 .138.146.127 suggesting a potential regulatory mechanism for BDNF through CRE-mediated gene transcription. which has been 339 . the SSRI fluoxetine prevented the neurotoxic effects of ecstasy (3.140 MAOIs (eg.139 Mechanistically.134 Interestingly. BDNF itself also possesses antidepressant-like effects in rodent models used to screen antidepressants following direct infusion into either the midbrain136 or hippocampus.128-133 A recent study found that exercise-induced upregulation of BDNF at the mRNA and protein level and phosphorylation of survival factor Akt both occurred via a CREB-dependent mechanism.Beneficial effects of psychotropic agents . ECT increased BDNF and its receptor (trkB) in the hippocampus.2.6-tetrahydropyridine (MPTP)induced dopaminergic neural toxicity. A very recent study found that suppression of the gene disrupted in schizophrenia 1 (DISC1).149 ECT was similarly found to increase neurogenesis in nonhuman primates. serum levels of BDNF levels are decreased in unmedicated depressed patients compared with depressed patients currently taking antidepressants or healthy controls. the SNRI reboxetine also depends on CREB activation (phosphorylation) in order to show similar changes in BDNF and Akt.147 ECT also increased neurogenesis in rodents. infusing a blocking anti-IGF-1 antibody reduced the protective effects of exercise.126 A similar effect was also found following chronic (21 days) but not acute treatment with different classes of antidepressants (the MAOI tranylcypromine. 2009 their therapeutic effects. Interestingly. Furthermore. Chronic treatment with the SSRI fluoxetine.141 Interestingly.Hunsberger et al Dialogues in Clinical Neuroscience . No. at least 2 weeks of fluoxetine treatment was required to enhance neurogenesis. Ladostigil. Antidepressants affect prominent signaling cascades involved in neuronal protection and survival As noted above. BDNF.144 These protective effects depended in part on the neurotrophic factor insulin-like growth factor I (IGF-1).135 BDNF serum levels were also found to be negatively correlated with depression scores as assessed by the Hamilton Depression Rating Scale (HDRS). Exercise has also been reported to upregulate many factors in the MAPK signaling pathway including BDNF. may result from activation of p38 MAPK.5. activation of the MAPK/ERK and Wnt/GSK signaling cascades (Figure 1) ultimately targeted by antidepressants may result in enhanced neuroprotective and survival mechanisms.4-methylenedioxymethamphetamine.151 The molecular mechanisms underlying these antidepressant-induced enhancements in neurogenesis may involve the MAPK/ERK and/or Wnt/GSK-3 pathways. which may enhance neurotrophic and neuroprotective mechanisms in addition to neurogenesis. and the TCA desipramine). reportedly activated Bcl-2 family members and BDNF142 in addition to ERK1/2 (p44/42 MAPK). the SSRI sertraline. nialamide. and GDNF. pargyline.

however.164 while another study found that rTMS augmented BDNF in drug-resistant patients. the selective serotonin reuptake enhancer (SSRE) tianeptine prevented the decreased brain metabolites (NAA. it is likely that these drugs improve many facets of psychosis through mechanisms beyond their fundamental interaction with dopaminergic. 147 In another study. recent findings suggest these improvements may emerge more rapidly than previously believed. glutamate.153 Curiously. which bind to a broader group of receptors. and retrieval) but no overall IQ differences when compared with controls160. Several typical antipsychotics have a higher dopamine D2 receptor affinity than atypical antipsychotics. or classic neuroleptics) or atypical (second generation).162 Interestingly. creatine.145.169 These effects are less common with atypical antipsychotics. these data suggest a more complicated picture that requires a better understanding of proper BDNF function (and not just its expression).154 In a mouse model of the BDNF-Met variant in which BDNF-Met was expressed at normal levels. In tree shrews. 66Met allele carriers have a lower neuronal distribution of BDNF in addition to decreased activity-dependent BDNF secretion. MRI studies found that these PTSD patients had an 8% smaller right hippocampus than controls.163 Finally. conventional. the polymorphism in the BDNF gene (val(66)met) has also been associated with reduced hippocampal volume. longterm storage. which also have 340 . Notably. Given the hypothesis that antidepressant effects are partially mediated through enhanced BDNF secretion. serotonin. In one study. total recall. phosphocreatine).158. and schizophrenia. a recent meta-analysis found enhanced antidepressant response in the Met variant of the BDNF 66Val/Met polymorphism in individuals with MDD.166 While antipsychotics can have an immediate impact on symptoms such as agitation. it would seem contradictory that 66Met allele carriers. but regulated secretion from neurons was reduced.157 and which may ultimately contribute to the hippocampal damage and volumetric changes reported in the literature. this BDNF polymorphism was also associated with decreased episodic memory performance.159 suggesting that the stress associated with depression may have contributed to these volumetric changes. decreased neurogenesis by acting through GSK3β.155 Taken together. it often takes weeks before improvement is seen in other symptoms. and muscarinic receptors. as well as the potentially irreversible condition known as tardive dyskinesia. major depressive disorder (MDD). antidepressants can reverse some of these changes. which is thought to result from a dysfunctional hypothalamic-pituitaryadrenal (HPA) axis negative feedback circuit. repetitive transcranial magnetic stimulation (rTMS) has also shown putative neurotrophic properties in patients with MDD. serotonergic. and normalized corticosterone levels and behavioral deficits.156. Chronic treatment with conventional antipsychotics can lead to adverse extrapyramidal side effects (EPS). lower hippocampal activation (as measured by fMRI). and these reductions correlated with total duration of depression but not with age. suppressed neurogenesis. muscarinic. Subjects with MDD were found to have significantly smaller hippocampal volumes. normal BDNF function does appear to be important for proper hippocampal function and mood regulation. which mimic the neurodegenerative disorder Parkinson’s disease. however. such as delusions. severely depressed patients show elevated levels of the stress hormone cortisol. Further support for this notion comes from studies reporting that individuals with post-traumatic stress disorder (PTSD) had impaired hippocampal function (deficits in short term memory. In addition to enhanced antidepressant treatment response.168 As with mood stabilizers and antidepressants.165 Antipsychotics Antipsychotic medications are traditionally categorized as typical (also known as traditional. and other receptor families. with their attenuated BDNF secretion. including dopamine.Pharmacological aspects implicated in BPD.161 In addition. α-adrenergic. histamine.167. blocked inescapable foot shock stress-induced decreases in hippocampal neurogenesis. rTMS improved refractory depression by augmenting catecholamines and BDNF. and lower hippocampal NAA levels in humans. and reduced hippocampal volume associated with chronic psychosocial stress. fluoxetine was unable to ameliorate a stressinduced anxiety phenotype. have a more robust response to antidepressants.152 Antidepressants and the reversal of stress-induced changes in neuronal plasticity In terms of clinical implications. chronic treatment with antidepressants induced hippocampal neurogenesis.

One recent study noted that.174 Neuroprotective properties have also been demonstrated for the atypical antipsychotic olanzapine against various insults.182.185 In vivo investigations have further noted that brain regions like the striatum.173 Interestingly. such as risperidone and quetiapine. For example. SH-SY5Y. and PI3K following olanzapine treatment. atypical antipsychotics also have their own adverse metabolic side effects like weight gain and diabetes.187 Other studies found the opposite effect.191 Olanzapine also upregulated the expression of Bcl-2 in rat frontal cortex and the hippocampus. transitioning to the atypical antipsychotics olanzapine or risperidone appeared to rescue BDNF expression back to near baseline levels. and brain region under consideration. the findings suggest that antipsychotics can alter prominent intracellular cascades and ultimately induce neurotrophic or neurotoxic responses in vivo and in vitro. that chronic treatment of rats with haloperidol increased striatal volume.194 Overall.178 Many studies have assessed the effects of antipsychotics on neurotrophic factors such as BDNF and nerve growth factor (NGF). including ERK/MAPK. and limbic structures were some of the most drastically altered cytoarchitecturally by conventional antipsychotics.192. such as oxidative stressors190 and ischemia.Hunsberger et al Dialogues in Clinical Neuroscience . and their more diverse set of responses make critical evaluations more challenging (see ref 183). Multiple studies in phenochromocytoma (PC12) cells have also noted upregulation of pERK1/2.197 although a study that used osmotic pumps 341 . inducing apoptosis and reducing cell viability.176. pAkt.184 Studies have demonstrated that chronic or high doses of typical antipsychotics. including Bcl-2. have neuroprotective properties that might be relevant to their clinical efficacy.188 In contrast. as well as the expression of BDNF in the hippocampus. one study found that the effects of stress-induced decreases of BDNF could be prevented by pretreatment with quetiapine. most prominently in the parietal and frontal brain lobes. can be neurotoxic. 172 while chronic treatment with the atypical antipsychotic olanzapine increased pERK1/2 levels in rat prefrontal cortex (PFC). Though the mechanism remains unclear.195 but not in the rat hippocampus. No. Antipsychotics alter the expression of prominent intracellular cascades and influence neuroplasticity and neuroprotection in animal models Studies conducted in rodents and cell lines have demonstrated that some antipsychotics can induce significant changes in intracellular cascades that are involved in neuroplasticity and neuroprotection against excitotoxic insults. after chronic (90-day) treatment with haloperidol. and BDNF pathways.Beneficial effects of psychotropic agents . Typical antipsychotics such as haloperidol tend to reduce BDNF expression in regions of the hippocampus 179-181 and striatum.174. high doses of haloperidol induced apoptosis in the striatum and substantia nigra of rats treated via acute intraperitoneal injection.171 As highlighted below.196.Vol 11 . quetiapine.193 For instance. atypical antipsychotics appear to have some neuroprotective functions.175 Antipsychotics have also been shown to influence other prominent cascades discussed above.176 GSK-3. 3 . 2009 improved efficacy in treating the negative symptoms associated with schizophrenia. Effects of antipsychotics on neurogenesis in animals Initial studies detected increased neurogenesis in the gerbil hippocampus following haloperidol treatment. and for enhancing neuroprotection and neurogenesis in both animal studies and patient-based studies. though their overall benefit is still unclear170.182 Atypical antipsychotics do not consistently downregulate BDNF. these two classes of antipsychotics show markedly different profiles for activating neuroplasticity cascades.181 Studies have suggested that other atypical antipsychotics. Browning and colleagues observed decreases in pERK1/2 following either a single injection of olanzapine or haloperidol (a typical antipsychotic). Acute treatment with the atypical antipsychotic clozapine led to increased levels of active (phosphorylated) MEK1/2 in rat prefrontal cortex.186 Macaque monkeys treated for 17 to 27 months with therapeutic levels of either haloperidol or olanzapine had reduced brain volumes by ~10%. but chronic haloperidol did not alter pERK1/2 levels. and have noted significant differences between typical and atypical antipsychotics. pretreatment with the atypical antipsychotics clozapine. and 3T3 cells following a number of death-inducing treatments. Bcl-2. or risperidone prevented PC12 cell death following serum withdrawal. depending upon the drug conditions.189 while olanzapine reduced cell death in PC12. Akt. like haloperidol and reserpine.145 Two more recent studies found that haloperidol did not affect neurogenesis. hypothalamus.177 and CREB. time course.

In fact. but do not necessarily increase neuronal survival or differentiation into adult neurons. There is hope that these clinically safe and widely used agents will slow disease progression. One study of patients with first-episode psychosis found that treatment with haloperidol reduced grey matter volume. is well-known to be associated with reduced regional volumes. to elucidate the effects of chronic antipsychotic treatment. and human studies described in this review support the notion that psychotropic agents used to treat the major psychiatric disorders—especially mood stabilizers—are associated with significant neurotrophic/neuroprotective effects. Closing remarks The growing data from molecular.205 Another recent study found that olanzapine increased NAA in the prefrontal cortex of remitted adolescent patients with mania compared with nonremitted patients.202 Schizophrenia. olanzapine-treated patients showed no significant reductions compared with controls. Chronic treatment of rats with clozapine or olanzapine.198 Furthermore. this finding needs further replication because the primary aim of the study—a NAA increase following olanzapine treatment. neuroprotection is the most consistent biological outcome associated with lithium treatment. in contrast.Pharmacological aspects (instead of daily intraperitoneal injections or delivery in drinking water) found that haloperidol increased neural stem cell (NSC) proliferation in the adult rat forebrain. see ref 186. it is possible that the NAA increase seen in responders was more closely related to improved mood than to olanzapine’s neurotrophic properties. augmented the number of BrdU-labeled cells in the dentate gyrus196 or prefrontal cortex and dorsal striatum. Quetiapine has also been shown to reverse the inhibition of hippocampal neurogenesis caused by chronic restraint stress. studies suggest that there are differences in the brain volumes of patients treated with antipsychotics compared with controls. brain volume. and inhibit GSK-3 alpha and 342 . suggesting that under certain conditions. for a thorough analysis. haloperidol could promote neurogenesis through its suppression of D2-mediated pathways that normally prevent NSC proliferation. no differences were found in other brain regions. Bcl-2. or within groups of patients treated chronically with typical versus atypical antipsychotics. increased ventricle size. independent from clinical change—was negative. the researchers demonstrated that this proliferation was mediated through D2 receptor stimulation in vitro. and BAG-1 expression. several clinical trials are being conducted to evaluate the feasibility of using lithium and valproate to treat a variety of neurodegenerative diseases. mature neurons in the weeks following treatment with antipsychotics. and density in patients Studies conducted with schizophrenic patients have examined NAA measures and volumetric brain changes using 1H-MRS and MRI. the disorder most often treated with antipsychotics. block HDAC activity (valproate only).199 Effect of antipsychotics on NAA levels. Furthermore. Atypical antipsychotics have shown a more consistent profile of enhancing neurogenesis. for example. psychotropic agents developed for the treatment of neurodegenerative illnesses may be beneficial as therapeutics for major psychiatric illnesses. in addition to their proven ability to treat psychiatric disorders. cellular. Similarly. neither found a significant difference in the number of BrdU-positive. Currently. and significantly increase the number of BrdU-labeled immature neurons detected compared with vehicle-treated. because lithium and valproate stimulate the ERK and PI3K pathways. These effects may enhance cellular resilience and plasticity in dysfunctional synapses and neural circuitry implicated in psychiatric disorders. these agents may be useful in the treatment of neurodegenerative illnesses and ischemia.206 Although this suggests a possible in vivo neurotrophic effect.197 Although both studies detected increased proliferation of precursor cells. The crux of such research is that. Indeed. Overall. increase BDNF. respectively.203 and deteriorating course. Patients treated with atypical antipsychotics had higher NAA measures in the frontal lobes200 and anterior cingulate gyrus201 than those treated with typical antipsychotics. Another study measured NAA changes during antipsychotic treatment and after cessation for at least 2 weeks in individual patients using a within-subject design and found significant decreases (~9%) in NAA levels in the dorsolateral prefrontal cortex after ending antipsychotic treatment.204 making it difficult to distinguish volumetric changes induced by antipsychotic treatment. and perhaps produce functional improvements. stressed rats. animal.

343 . si ce n’est toutes. les antidépresseurs et les antipsychotiques. Ellos también promueven la neurogénesis y son protectores en modelos de enfermedades neurodegenerativas e isquemia. financial or otherwise. les psychotropes.Beneficial effects of psychotropic agents . comme les régulateurs de l’humeur. gaining insight into rapid-act- ing versus long-term compensatory changes facilitated by these psychotropic agents will pave the way for the next generation of therapeutics. como también los niveles de N-acetil aspartato y glutamato en determinadas regiones cerebrales. La plupart de ces preuves. whose dual nature will provide both a rapid treatment response to restore function. continued study of these agents may elucidate other clinically relevant targets. Estos agentes también regulan hacia arriba la expresión de moléculas tróficas/protectoras como el factor neurotrófico cerebral. Elles favorisent aussi la neurogenèse et exercent un effet protecteur dans les maladies neurodégénératives et l’ischémie. 2009 beta activities. la protéine BCL2 (B-cell lymphoma 2).Vol 11 .Hunsberger et al Dialogues in Clinical Neuroscience . Además. la proteína 2 del linfoma de células B. el factor de crecimiento neural. De plus. The authors have no conflicts of interest. as well as support long-term changes to maintain successful treatment and prevent relapse. antidepressants. la kinase PI3 et la Wnt/GSK (wingless/kinase glycogène synthase). Additional data are also needed to understand whether the neurotrophic and neuroprotective effects of mood stabilizers. La mayor parte. des études d’imagerie sur l’homme ont montré que ces agents augmentaient le volume et la densité du tissu cérébral ainsi que les taux de N-acétyl aspartate et de glutamate dans les régions cérébrales sélectionnées. Finally. Tomados en conjunto. sino toda esta evidencia se recolectó a partir de estudios animales que utilizaron esquemas terapéuticos clínicamente relevantes. estos datos sugieren que los efectos neurotróficos/neuroprotectores de estos fármacos tienen un gran potencial terapéutico en el tratamiento no sólo de los trastornos del ánimo y de la esquizofrenia. No. Au total. la quinasa serina-treonina y el atanogen 1 asociado a Bcl-2. la kinase sérine-thréonine et le BAG-1 (athanogène 1 associé à BCL-2). le NGF (nerve growth factor). 3 . en humanos los estudios de imágenes han encontrado que estos fármacos aumentan el volumen y la densidad del tejido cerebral. Effets neuroprotecteurs et neurotrophiques des psychotropes D’après un nombre croissant d’arguments. and to what extent their neurotrophic/neuroprotective effects contribute to their therapeutic action. Ces voies régulent également positivement l’expression des molécules trophiques/protectrices comme le BDNF (brain-derived neurotrophic factor). sont issues d’études animales utilisant des schémas thérapeutiques cliniquement pertinents. Los efectos neurotróficos y neuroprotectores de los agentes psicotrópicos La evidencia acumulada sugiere que los agentes psicotrópicos como los estabilizadores del ánimo. ces données suggèrent que leurs effets neurotrophiques/neuroprotecteurs ont un potentiel thérapeutique large non seulement dans les troubles de l’humeur et la schizophrénie mais aussi dans les maladies neurodégénératives et l’ischémie. and antipsychotics are cell-type or circuitry specific. to disclose. ultimately leading to improved treatments for these devastating disorders. la quinasa PI3 y las vías de señales de la wingless/glicógeno sintetasa quinasa 3 (GSK). exercent leurs effets neurotrophiques et neuroprotecteurs en activant 3 voies de signalisation : la MAP (mitogen activated protein)/ERK (extracellular signal-related) kinase. e inactivan moléculas proapoptóticas como la GSK-3. los antidepresivos y los antipsicóticos producen sus efectos neurotróficos/neuroprotectores mediante la activación de la quinasa relacionada con la señal de la proteinquinasa/extracelular activada por mitógeno. ❏ Acknowledgements: Funding for this work was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH). sino que también en enfermedades neurodegenerativas y en la isquemia. et des molécules proapoptotiques inactivées comme la GSK-3.

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sensitization. PA 19104-6178. University of Pennsylvania. O’Brien. In the past. often lasting for years. USA Address for correspondence: Prof Charles P. and most common. Department of Psychiatry. clinicians considered detoxification to be the treatment for addiction.upenn.trc. O'Brien. 3900 Chestnut Street. learning. The clinical significance of these brain changes is that addiction. becomes a chronic illness with relapses and remissions. 2009. tolerance. Treatment Research Center. memory. This has been demonstrated directly in animal models and indirectly in human brain imaging studies. University of Pennsylvania. only a minority of users progress to the stage of compulsive use or addiction. This intense activation produces learned associations to cues that predict drug availability. The first. Two general forms of neuroplasticity can be demonstrated.edu) Copyright © 2009 LLS SAS. However. Treatment Research Center. resulting in motivation to resume drug-taking behavior when drugrelated cues are encountered. detoxification is simply removal of the drug from the body and treatment of withdrawal symptoms. reinforcement Author affiliations: Department of Psychiatry. The central nervous system changes underlying this conditioned behavior are just beginning to be understood. is tolerance accompanied by physical dependence. New treatments aimed at this neuroplasticity are being tested in animal models. It therefore requires chronic treatment with medications and behavioral therapies based on an understanding of the fundamental nature of these changes in the brain. especially the reward system. This was first demonstrated in animal models. LLS SAS Dialogues Clin Neurosci. PhD Compulsive drug-taking behavior develops in vulnerable individuals who ingest substances that activate the reward system. once established.11:350-353. All rights reserved ddiction is a disease of neuroplasticity. This form of plasticity occurs in all individuals when cer- A 350 . Philadelphia. and later shown in human addicts more than 30 years ago. conditioning. MD. Keywords: addiction. © 2009. relapse.1 Addiction is fundamentally a memory trace that manifests itself by reflex activation of brain circuits. Now we know that the essence of addiction continues long after the last dose of the drug. A characteristic of all drugs that are abused by humans is that they activate dopamine circuits in brain reward systems by a variety of mechanisms. leading to a drive toward drug-taking. Tolerance is manifested by reduced effects from a given dose that is given repeatedly. but vulnerability to this disorder is influenced by complex genetic and environmental variables. Drugs that activate the reward system carry liability for the development of addiction. but dopamine has received the greatest attention. Pennsylvania. USA (e-mail: obrien@mail. Other neurotransmitters are also involved. and “physical” dependence (not addiction) is manifested by withdrawal symptoms when the drug is stopped abruptly. While a given drug of abuse will tend to have very similar immediate effects in all users.Brief report Neuroplasticity in addictive disorders Charles P. Philadelphia. With repetition the reward system becomes reflexively activated by cues alone. dependence.

sedatives.4 During brain reward system activation. as well as commonly abused drugs such as alcohol. The second form of neuroplasticity is manifested by compulsive drug-seeking behavior. Chronic morphine given to rats. Thus.2 Thus.3 Even cues so brief that they do not reach consciousness (33 msec) can produce rapid activation. This is considered to be a model of “relapse” in human addicts.org 351 . An important feature of this form of neuroplasticity is that it is stable and perhaps permanent.Vol 11 . Shaham and colleagues have studied the relapse or reinstatement of drug-taking in rats trained to self-administer intravenous cocaine. has been found to reduce dendritic spines (whereas stimulants increased spines) on ventral tegmental area neurons. the addict reports drug craving. After the extinction process is complete. 2009 tain drugs are taken repeatedly. for example. Transcription factors have been observed to be changed by addictive drugs. and may be involved in long-term changes associated with drug-seeking behavior. antidepressants. even years after the last dose of the drug. Evidence of the plasticity that has occurred with the development of addiction can be demonstrated by brain imaging studies that show rapid activation (increased blood flow to reward pathways) when drug-related cues are shown to addicts who have been free of drugs for at least a month. as measured by displacement of labeled raclopride in positron emission tomography (PET) studies. reinforces adaptive behavior such as that leading to the acquisition of water. the drug experience becomes associated with environmental cues and acquires increasing salience. Chronic morphine also reduces neurogenesis in the hippocampus. The strength of the craving is related directly to the amount of endogenous dopamine released in reward structures. Delta Fos B accumulates in dopamine terminals in the cortex and striatum. Individuals who develop this neuroplasticity tend to suffer from a chronic illness with potential for relapse. which developed early in evolution.dialogues-cns. Eventually. The reward system. and to continue with repeated exposure rather than diminish. These changes persisted during abstinence.5 More direct studies of the plasticity induced by drugs of addiction can be seen in animal models. thus. the cocaine can be turned off. The intensity of relapse can be measured by the number of times the light causes the rat to press the bar despite not receiving any cocaine. these transcription factor changes do not seem to underlie long-term neuroplasticity. In the nucleus accumbens. expected rewards. the animal can be tested for reinstatement by returning it to the drug-taking environment and giving the light cue. with return to prior levels when the drug is no longer present. cocaine. The latter is the increase in motor behavior in response to repeated. Changes in neuronal morphology have also been noted in animals exposed to drugs that are abused. The dopamine release caused by a drug of abuse tends to be greater than that of natural rewards. The authors also found that exposure to cocaine cues increased extracellular signal-related kinase (ERK) in central amygdala after 30 days of rest. and sex. It was found that reinstatement occurred when rats were tested 1 week after extinguishing cocaine-seeking.Neuroplasticity in addictive disorders . The strengthening of relapse tendency over time has been called “incubation” and is associated with increases in the levels of the growth factor brain-derived neurotrophic factor (BDNF) in the ventral tegmental area and in the nucleus accumbens. food. which appears to be involved in the development of motivated behaviors. After the behavior is well trained. 3 . No.O’Brien Dialogues in Clinical Neuroscience .10 These changes may be the basis for the cognitive losses www. and nicotine. This shows that there is an active neuroplastic process in the brain that increases over time and is manifested by increased cocaine-seeking behavior. and progressively increased further if the rats were allowed to rest in their cages for up to 6 months before relapse testing. Examples include prescribed medications such as β-blockers.7 All drugs of abuse tested produce an increase in delta Fos B. and opioids for pain. The delta Fos B changes are temporary. Disruption of this process blocks the development of drug-associated plasticity such as behavioral sensitization. fixed doses of a stimulant.8 Genes directly regulated by delta Fos B appear to have different effects and may limit as well as promote drug reinforcement. as is the case with natural. but the reinstatement was significantly greater at 4 weeks. Drug-taking then acquires more salience than natural or adaptive behaviors. Drugs that directly activate the reward system may produce learning that diverts the individual to those behaviors that repeat the drug-induced feelings of reward. pushing the lever no longer provides cocaine. an increase in dendritic spine density has been reported in medium spiny neurons from rats self-administering cocaine.9 Changes in neuronal morphology have also been found in individuals chronically exposed to opioids.6 Availability of cocaine is signaled by a light that the animal then associates with cocaine. the unrewarded bar pressing stops. but not after 1 day.

they reported a reduction in glutamate in the brains of animals exposed to long-term cocaine and a disruption of glutamate homeostasis. it was available to be administered to cocaine addicts presented with cocaine-related cues in an attempt to translate findings in the animal model to human addicts. Using rats trained to selfadminister cocaine.16 Further clinical trials are in progress. as well as a normalization of the AMPA:NMDA ratio. By providing feedback of frontal activation. which in turn could facilitate establishing behaviors that might compete with drugseeking.12 In addition. Since the learned addictive behavior is thought to result from neuroplasticity such as that described above. A very interesting animal model of this approach has been illustrated by a series of experiments by Kalivas et al. Those treated with N-acetyl cysteine reported reduced desire for cocaine compared with the control group. Following withdrawal from chronic cocaine there is a marked imbalance in glutamate homeostasis. All rights reserved 352 .11 The imbalance in glutamate homeostasis is associated with a reduction in basal extracellular glutamate levels and a potentiated release of synaptic glutamate during drug-seeking. Cystine can be administered to animals withdrawn from chronic cocaine using Nacetylcysteine as a carrier. The treatment also prevents changes in spine head diameter induced during cocaine-seeking. it seems logical to consider reversal of these changes as a target for the treatment of addictive behaviors. but cocaine-dependent patients are unable to inhibit craving when shown drug-related stimuli. By restoring the glutamate homeostasis in this manner. The continued study of the underlying mechanisms of plasticity will undoubtedly produce other novel pharmacological and behavioral treatments. Exogenous N-acetyl cysteine is used for the treatment of hepatic failure in acetaminophen overdose. Normal subjects can activate frontal control mechanisms when attempting to inhibit sexual arousal. Thus. This represents a therapeutic attempt to introduce new learning to control addictive behavior. and this correlates with decreased frontal lobe activity. there is a basal increase in the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) to N-methyl-D-aspartic acid (NMDA) current ratio and a loss of both long-term potentiation (LTP) and long-term depression (LTD).Brief report seen in some patients receiving chronic opioids for pain.13 There are therapeutic implications in these observations on glutamate homeostasis. The treated animals also show a restored ability to induce LTP and LTD. the data above suggest the possibility that normalization of glutamate homeostasis in addicts might restore the ability to induce synaptic plasticity in the nucleus accumbens. or glutamate uptake can be increased by the antibiotic ceftriaxone. ❏ Copyright © 2009 LLS SAS. reinstatement of cocaine seeking is prevented. with both cystine-glutamate exchange and glutamate uptake being reduced in the nucleus accumbens.17 Addicts have been shown to have poor ability to inhibit impulses. Another attempt to reverse the learned behaviors seen in addiction involves a new technology of real-time functional magnetic resonance imaging biofeedback of brain activity. N-acetyl cysteine was found to reduce pathological gambling15 and cigarette smoking. the patients will attempt to learn to activate inhibitory structures and inhibit drug craving.14 In another human study.13 Taken together.

Nestler EJ. RN. se comporte comme une maladie chronique avec rechutes et rémissions.23:3531–3537. McFarland K. Neuroplasticité et troubles addictifs Les comportements compulsifs de prise de substance se développent chez des individus vulnérables qui ingèrent des substances activant le système de récompense.62:652-657. Nat Neurosci. Kim SW.2876-2884.412:141-142. Wells B. 8. 2000. Nestler EJ. et al. Fitzgerald J. Self DW. Myrick H. McFarland K.29. Neuroadaptation. Testa T. Wise RA. REFERENCES 1. deCharms RC. Wang G-J.97:7579-7584. 4. Mardikian P. Moussawi K.2:119–128. Grant JE. O'Brien TJ. Robinson TE. 2008. in the treatment of pathological gambling: a pilot study. Grimm JW. Kalivas PW. favoreciendo el camino hacia el consumo de drogas. et al. Volkow ND. 2001. 2004. Proc Natl Acad Sci U S A. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. Les modifications du système nerveux central qui sous-tendent ce comportement conditionné commencent seulement à être comprises. 14.9:720-729. Childress AE. 9. 16. le système de récompense s’active de façon réflexe par les seuls signaux. El significado clínico de estos cambios cerebrales es que la adicción. et al. Nat Rev Neurosci. 2009. Altered dendritic spine plasticity in cocaine-withdrawn rats. Am J Psych. 3 . O’Brien CP.164:1115-1117. Hope BT. De nouveaux traitements ciblant cette neuroplasticité sont en train d’être testés dans des modèles animaux. 2009 Neuroplasticidad en los trastornos adictivos La conducta compulsiva de consumir drogas se desarrolla en individuos vulnerables que ingieren sustancias que activan el sistema de recompensa. J Neurosci.6:1208–1215. 15. 2003. Kalivas PW. Am J Physiol. No. Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Bouknight A. et al. 2008. Ceci nécessite donc un traitement chronique avec des médicaments et des thérapies comportementales basées sur la compréhension de la nature fondamentale de ces modifications cérébrales.org . Zahm DS. 3. LaRowe S. Opiates inhibit neurogenesis in the adult rodent dentate gyrus. Ehrman. provoquant une pulsion de prise de drogue. Nat Rev. a glutamate-modulating agent. Recién se están comenzando a comprender los cambios del sistema nervioso central que subyacen a esta conducta condicionada. 2006. Lapish CC.O’Brien Dialogues in Clinical Neuroscience .841-845. 2.26:6583-6588. N-acetyl cysteine. Molecular basis of long-term plasticity underlying addiction. Incubation of cocaine craving after withdrawal. 17. 13. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. una vez establecida. Con la repetición. Neuroadaptations in cystine– glutamate exchange underlie cocaine relapse. Applications of real-time fMRI. llega a ser una enfermedad crónica con recaídas y remisiones. Barrot M. 6. el sistema de recompensa se activa en forma refleja sólo por las señales. 1999. 353 www. McClung CA. Biol Psych. LaRowe SD. Limbic activation during cue-induced cocaine craving. Cette activation intense entraîne des associations à des signaux qui indiquent la disponibilité de la drogue par un phénomène d’apprentissage. Hedden S. 1977. McElgin W. Is cocaine desire reduced by N-acetylcysteine? Am J Psych. Kolb B. Schad. Shaham Y. 2007. Toda S. une fois installée. Baker DA. 2003.47(suppl 1):33–46. Nat Neurosci. Schultz W. Nature. Eisch AJ. Odlaug BL.6:743– 749. 11. Prelude to passion: limbic activation by “unseen” drug and sexual cues. Ces modifications cérébrales signifient cliniquement que l’addiction. Structural plasticity associated with exposure to drugs of abuse. En modelos animales se están evaluando nuevos tratamientos orientados a esta neuroplasticidad. Lake RW. Avec les répétitions du processus. J Neurosci. Esta patología requiere por lo tanto de un tratamiento crónico con medicamentos y terapias conductuales basadas en una comprensión de la naturaleza fundamental de estos cambios en el cerebro. Esta intensa activación produce asociaciones aprendidas frente a señales que predicen la disponibilidad de droga.Neuroplasticity in addictive disorders . 1998. Knackstedt LA. 7. 2008. et al. Childress AR. PLoS ONE.156:11-18. Predictive reward signal of dopamine neurons. Nestler E. The role of cystine-glutamate exchange in nicotine dependence in rats and humans.80:1–27. Neuropharmacology. Mozley PD. O'Brien CP.65. Revich M. Brady JP. Wang Z. 10.Vol 11 .3:e1506. Conditioned narcotic withdrawal in humans. J Neurosci.195:1000-1002. 12. 5.dialogues-cns. Teland F. Shen H-W. Science. Biol Psych. CA. 2003. 2001. 2007.

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biological.org Supported by an educational grant from Servier w w w.Dialogues in clinical neuroscience An interface between clinical neuropsychiatry and neuroscience. s e r v i e r. c o m . providing state-of-the-art information and original insights into relevant clinical. and Psychotropics 2000 • Posttraumatic Stress Disorder • Alzheimer’s Disease • From Research to Treatment in Clinical Neuroscience • Schizophrenia: General Findings 2006 2001 • Genetic Approach to Neuropsychiatric Disorders • Schizophrenia: Specific Topics • Cerebral Aging • New Perspectives in Chronic Psychoses • Diagnosis and Management of Schizophrenic Disorders • Depression in Medicine • Drug Discovery and Proof of Concept • Stress 2007 2002 • • • • • • • • Pathophysiology of Depression CNS Aspects of Reproductive Endocrinology Anxiety I Drug Development Dementia Psychiatric Disorders in Somatic Medicine Anxiety II Chronobiology and Mood Disorders • Neuropsychiatry and Cardiovascular Disease • Neuropsychiatric Manifestations of Neurodegenerative Disease • Chronobiology in Psychiatry • Addictive Substances 2003 2008 • • • • Epilepsy and Psychiatry Developments in Bipolar Disorder The Core of Depression Remission in Depression 2004 • Predictors of Response to Treatment in Neuropsychiatry • Neuroplasticity 2009 • Child and Adolescent Psychiatry • Alzheimer's Disease and Mild Cognitive Impairment Back issues are available in pdf format on www.dialogues–cns. Neuropsychiatry. and therapeutic aspects • Parkinson's Disease 1999 • Bipolar Disorders • Depression in the Elderly • Nosology and Nosography • Mild Cognitive Impairment 2005 • Early Stages of Schizophrenia • New Psychiatric Classification based on Endophenotypes • Pharmacology of Mood Disorders • Sleep Disorders.

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11:1017-1030. Role of astrocytes in estrogen-mediated neuroprotection. 2005. Belcredito S. Maggi A. 2008. Czlonkowska A. Ciesielska A.14:228-235. et al. 27. 2008. 26. Curr Pharm Des.100:9614-9619. Proc Natl Acad Sci U S A. 3 . Toran-Allerand CD.108:327-338. Vegeto E. Gromadzka G. Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases. et al. No. 2006. 20. Meda C.42:70-75. Butts CL. 2008. 303 . Brann DW. et al. Duchateau J. Exp Gerontol. 2007. Morissette M. 2004. J Comp Neurol. Neuroendocrine factors alter host defense by modulating immune function. McCullough LD. D'Astous M. Estrogen and cytokines production . Yu J. Hurn PD. Endocrinology. Estrogen receptor-a mediates the brain antiinflammatory activity of estradiol. Vegeto E. Front Neuroendocrinol. Estrogen and ischemic neuroprotection: an integrated view. Ghisletti S.Vol 11 .500:1064-1075.29:507-519. The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation. Estrogen receptor alpha. 2007. 23. 28. 25. Minireview: a plethora of estrogen receptors in the brain: where will it end? Endocrinology. 19. Benedusi V. Vegeto E. 2001.147:2263-2272. 2003. Suzuki S. et al. 2009 18. 24. Trends Endocrinol Metab. Maggi A. Proc Natl Acad Sci U S A.Estrogen and stroke injury .145:1069-1074. Dubal DB. 2003. Bottner M. Sternberg EM. Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. 29. Cytokines and brain injury: invited review. Kurkowska-Jastrzebska I.Wise et al Dialogues in Clinical Neuroscience . J Intensive Care Med. 22. Cell Immunol.23:236-249. Dhandapani KM. Etteri S. 2008. 21. Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Steroid Biochem Mol Biol. Kadhim HJ.the possible cause of gender differences in neurological diseases. Sebire G. Belcredito S. Le Saux M.252:7-15.98:1952-1957. Etteri S. Zhu H. not beta is a critical link in estradiol-mediated protection against brain injury. Gerhold LM.

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