Hindawi Publishing Corporation Neural Plasticity Volume 2011, Article ID 527605, 16 pages doi:10.


Review Article Altered GABA Signaling in Early Life Epilepsies
Stephen W. Briggs and Aristea S. Galanopoulou
Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center Rm 306, Bronx, NY 10461, USA Correspondence should be addressed to Aristea S. Galanopoulou, aristea.galanopoulou@einstein.yu.edu Received 7 February 2011; Revised 4 May 2011; Accepted 27 May 2011 Academic Editor: Laura Cancedda Copyright © 2011 S. W. Briggs and A. S. Galanopoulou. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAA signaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAA receptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAA signaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain.

1. Introduction
Epilepsy is a disease of recurrent seizures: that is, unprovoked episodes of aberrant synchronous excitation of brain regions that disrupt normal functioning [1, 2]. Epileptic seizures are thought to reflect a failure in the ability to maintain the balance between excitation and inhibition. The mechanisms underlying seizures are complex and not uniform across the numerous seizure types that exist [1]. Furthermore, our ability to study these mechanisms is often limited by the tools we can use: we can only see as far and as much as those tools allow. Consequently, many of the hypotheses describing the pathogenesis of seizures are biased by the dominant ictal phenomena, unbalanced excitation-inhibition and aberrant neuronal synchronization, which may not necessarily be the actual ictogenic mechanisms. Neurotransmitters involved in neuronal inhibition, such as GABA, have attracted the major focus of research aiming to decipher mechanisms involved in ictogenesis. Under certain conditions, and definitely not in the majority of cases, seizures may lead to epilepsy or neurodevelopmental deficits. The early periods of life,

when brain development is still incomplete, susceptibility to seizures is increased [3, 4]. However, a combination of biological factors (genetic, age-related processes, epigenetic or environmental factors) protect neurons from seizureinduced injury, epileptogenesis, or mortality to a greater extent than the adult brain is protected [5]. It is increasingly recognized that seizures may leave their imprint on the developing brain by altering the way that neurons differentiate, connect, and communicate to each other, even if, in many cases, such changes may be ultimately compensated for. As extensively outlined in the reviews included within this special issue, GABA plays a central role in controlling neuronal development and communications. A major focus of research has therefore been thrown into efforts to elucidate its role not only in ictogenesis but also in the pathogenesis of the sequelae of early life seizures, whether this may be epilepsy, cognitive, or behavioral deficits [6]. There are three types of GABA receptors reported in the literature: GABAA , GABAB , and GABAC , the latter classified more recently along with GABAA receptors, due to their functional similarities. Both GABAA and GABAC receptors

Immature neurons express predominantly chloride-importers. GABAA receptors are pentameric channels usually comprised of 2 α and 2 β subunits. GABAB is a metabotropic receptor that signals through cascades that modify potassium and calcium current (reviewed in [7]). 15]) (Figure 1). Paradoxical exacerbation of seizures by GABA-acting drugs has been reported in newborns. 24. CCCs are the electroneutral ion symporters that establish the chloride gradient between cells and their extracellular environment. or π subunits are present [11–13]. leaving NKCC1 as the most relevant chloride-importing cotransporter for the brain. In this review. such as NKCC1 [16]. GABAC are insensitive to bicuculline. based on the developmental patterns of the relative expression of NKCC1 and KCC2 [21. allowing chloride to flow in along its electrochemical gradient. θ .2 are ligand-gated ionotropic channels that allow primarily chloride but also bicarbonate to cross their pore in response to GABA binding. in whom the maturation of these systems is delayed compared to females. whereas PN60 rodents are considered young adults. The cytosolic carbonic anhydrase VII (CAVII) increases around postnatal day 12 (PN12) in the rat hippocampus [26]. During developmental maturation. by the end of the first postnatal week. we will discuss the bidirectional relationship of seizures to GABAA signaling at the level of the neurons. As a result. Each developmental process occurs at different tempos and is not always in synchrony with the above sequence of events. GABA-acting drugs. GABAA receptors. Multiple studies over the last few decades have confirmed that this electrochemical chloride gradient is developmentally regulated by changes in the expression of cation-chloride cotransporters (CCCs). with known representatives the NKCC1 and NKCC2. Chloride exporters are the potassium/chloride cotransporters (KCCs). generating a depolarizing Neural Plasticity response [12. but KCC2 is specific to neurons. generated by carbonic anhydrase. δ . There is considerable evidence that alterations in GABA signaling can cause seizures. The composition . with 4 known isoforms: KCC1-4 (reviewed in [11. This forces the open GABAA receptors to permit Cl− efflux through their channel pore. The immaturity of GABAergic inhibitory systems has been implicated in the heightened susceptibility of neonates to seizures and may also underlie the increased vulnerability of males. However. π ). and species/strain differences occur in the timing of this developmental shift. NKCC2 expression is specific to the kidney. GABA is depolarizing in the neonatal life and it stays depolarizing for longer developmental periods in the male brain than in females [17. 12. even if they may not always be as effective in newborn human babies as in older patients [21. There are 16 known mammalian GABAA receptor subunits (α1 − α6. as well as that seizures can change GABAergic signaling. ε. which generate high intracellular Cl− levels. 29–33]. or the sodium chloride cotransporters (NCCs). subcellular localization or affinity properties of each GABAA receptor complex. 10]. This makes KCC2 particularly interesting for the pathogenesis and therapy of neural diseases. is another negatively charged ion that can permeate the GABAA receptor. like the potassium/chloride cotransporter 2 (KCC2). when GABA opens GABAA receptors the ensuing influx of chloride results in hyperpolarizing currents [19] (Figure 1). However. the onset of puberty is at PN32-35 in rodents. 4]. rats are able to walk away from the nest. cell type. This is achieved because the intracellular chloride concentration is maintained at a low level. γ1 − γ3. The classical inhibitory GABAA signaling. 25]. when GABAA receptors open (Figure 1). For example. quite unlike the human newborns who cannot yet ambulate [27]. 2. such as benzodiazepines and barbiturates. direct migration [8]. and the ionic symporters that control chloride homeostasis and the efficiency of GABAA receptor mediated inhibition. especially in low weight premature babies [34]. The Immaturity of GABAA ergic Systems as an Age and Sex-Specific Risk Factor for Early Life Seizures Seizures are more common in the early periods of life and especially in males [3. ε. it is important to emphasize that this is a very oversimplified translation. Less frequently. which hyperpolarizes the cells. and control gene transcription [9. dominates over NKCCs [19–22].θ . This is thought to be due to shunting inhibition or inhibition via excitatory effects upon inhibitory interneurons [40]. The expression of GABAA receptor subunits changes with development and as a result the responsiveness of immature and adult neurons to GABAA ergic modulators are significantly different. giving rise to depolarizing GABAA responses [16–18]. Direct demonstration of the time of shift of GABAA receptor responses to hyperpolarizing has not been demonstrated in humans. There are 3 CCC classes. β1 − β3. though it is expressed ubiquitously. whereas the time of birth in rodents is considered to correspond to PN8-10. KCC1. KCC3 and KCC4 are widely expressed. 3. still remain the mainstay of treatments for neonatal seizures. however. based mostly on correspondence of protein and DNA content in the brain. In this review. Unlike GABAA receptors. Correspondence of Developmental Stages between Rodents and Humans To facilitate the translation of the experimental data into humans. we will focus primarily on GABAA receptors. Bicarbonate. the expression of chlorideextruding CCCs. rendering bicarbonate-mediated GABAA depolarizations more prominent [25]. 35–39]. The presence of a ρ subunit defines the GABAC receptors. though it has been suggested to occur before or soon after birth. whereas the fifth is either a γ or a δ subunit. The rodent infantile stage is thought to extend till PN21. sex. The chloride importing CCCs are either the sodium/potassium/chloride cotransporters (NKCCs). is due to chloride influx through the channel pore. it is worth reminding that the accepted correspondence of developmental stages between rodents and humans considers that the first week of life in rodents is equivalent to a premature newborn human. decreasing the intracellular chloride concentration [23]. 28]. as occurs in most adult neurons. which contribute towards the different pharmacokinetic. 14.

a disorder of GABAA signaling early in life may cause miswiring or malformations that predispose to seizures (Figure 2). Too much inhibition could also cause a seizure. has proconvulsant effects early in life and anticonvulsant in older animals and this switch occurs earlier in females [44. Panels c and d show the effects of NKCC1 activity on GABAA receptor function in the absence (panel c) or presence (panel d) of GABA. and by the Na+ /K+ ATPase. NKCC1 mediates the electroneutral cotransport of Na+ . 42]. As a result. as GABAA signaling is critical for brain development and early synaptogenesis [72–74]. Moreover. K+ . either by disinhibiting epileptogenic networks or via promoting neuronal synchronization ([67] reviewed by [68]). 45]. Many GABA-related mutations are known to cause early life epilepsy. 42– 46]. Their function is dependent upon the gradients of Na+ and K+ . membrane voltage. GABAA receptor subunit mutations have been implicated in childhood absence epilepsy (CAE) [50. of GABAA receptors is also different in newborns. proposed that loss of function mutations of the GABAA receptor subunits may have . Excessive inhibition has been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) ( [69] reviewed in [70]) or absence seizures [71]. the channel pore opens and Cl leaves the neuron. upon binding of GABA upon the GABAA receptor. causing a depolarization. as is thought to occur due to GABA release during seizures. Panels (a) and (b) show the effects of NKCC1 activity in the absence (panel (a)) or presence (panel (b)) of GABA. Activation of GABAA receptors therefore results into influx of Cl and hyperpolarizing current. like the substantia nigra pars reticulata (SNR). 75]. It is therefore important to investigate and clarify the exact molecular determinants that control GABAA inhibition in the young brain so as to optimize the treatment of seizures. 51. 78]).Neural Plasticity No GABA Na+ K+ Out NKCC 1 Na/K ATP-ase NKCC 1 In GABAA receptor Na K+ (a) + GABA 3 K+ 2[Cl− ] Na+ K+ 2[Cl− ] GABA Na/K ATP-ase NKCC 1 ATP ADP [Cl− ] ATP Na ADP K+ (b) GABAA receptor [Cl− ] Na+ K+ [Cl− ] Na+ K+ [Cl− ] KCC2 Na/K ATP-ase Out KCC2 In GABAA receptor Na/K ATP-ase GABA KCC2 GABAA receptor ATP ADP Na K+ (c) ATP Na ADP K+ (d) [Cl− ] [Cl− ] Figure 1: CCCs control GABAA receptor-mediated inhibition. Furthermore. Aberrant GABAA Signaling Predisposes to Seizures Clinical and experimental evidences indicate that an initial perturbation of GABAA signaling may facilitate seizures. which are controlled by various factors. and other epileptic syndromes (reviewed in Table 1 and [77. KCC2 in contrast exports K+ and Cl− reducing intracellular Cl− . rendering them less responsive to benzodiazepines [41. The excessive GABAergic stimulation of the SNR. including background conductances. and 2 Cl−. autosomal dominant epilepsy with febrile seizures plus (ADEFS+ ) [76]. These include loss of function mutations or deletions of GABAA receptor subunit genes that reduce their expression. increasing the intracellular Cl− concentration. amplitude or agonist sensitivity of GABAA currents. Chiu et al. the subcortical GABAergic networks that control seizures. have not fully developed [31. with less α1 and more α2/3 subunits. Conditional mutants indicate that the developmental period of exposure to insults that disrupt GABAA signaling may be critical in ictogenesis and epileptogenesis. A loss of inhibition could result in runaway excitatory circuits. or the duration. 4.

Infantile developmental effects in addition to their direct electrophysiological consequences [79]. seizures and epilepsy may ensue. Similarly. CAE CAE CAE ADJME Febrile. the investigators expressed the mutant allele for different periods of time. [47. ADEFS+ . Such observations are . This may rather reflect the indispensability of KCC2. a drug that acts as a GABAA receptor antagonist. 48] [49] [50– 52] [53] [49] [54– 59] [49] [60. KCC2bknockout mice demonstrate hyperexcitability at PN10 to PN16 (equivalent to human infantile age) [94] (Table 2). GAD65 or GAD67 loss suf-ficiently compensates for each other and does not appear to affect early brain development. at least in certain cases. Febrile Other mutations Stress-induced. a different hypomorphic mutation in KCC2 causes a lower PTZ threshold for induction of clonic seizures in mice. ADEFS+ IGE Childhood. Human linkage studies or transgenic knockout animal studies document that. of which KCC2b is thought to contribute to the developmental shift to hyperpolarizing GABAA receptor currents [106]. although these appear mostly in adults [88– 91]. Glutamic acid decarboxylase (GAD) isoforms GAD65 and GAD67 synthesize GABA in the brain. leading to increased seizure susceptibility [80–82]. 61] [62– 66] GABRG2 GABRP GAD65 knockout Mouse Human. KCC2 has two known isoforms. Although the expected intracellular accumulation of chloride and depolarizing shift of GABAA responses could easily explain the hyperexcitability. Knockout mice for the pyridoxal-5 -phosphate inducible GAD65 isoform. SMEI ADEFS+ . depending upon the genetic substrate. Juvenile Childhood Childhood Juvenile Infantile. despite the absence of gross morphological changes [95]. Dual GAD65/67 knockout mice are not viable [87]. as occurs in pyridoxine-de-pendency disorders [84.4 Table 1: GABA-related mutations linked with seizures. albeit. Febrile IGE. but also by exerting broader developmental effects. it has been proposed that GAD65 loss of function may preferentially decrease the presynaptic reserve pool of GABA and decrease the tonic GABA inhibition. 85]. compared to mice with late disruption of the γ2 subunit expression. have lower seizure threshold to picrotoxin. or spontaneous seizures that can be precipitated by stress [60]. Mice that were induced to express the mutant allele for longer developmental periods displayed higher seizure susceptibility to pentylenetetrazole (PTZ). childhood ? Age at first observation Neural Plasticity Ref. mouse Human ADJME. Ohtahara) 12 weeks Neonatal. Although no human GAD mutations have been found to consistently cause epilepsy [83]. due to the immaturity of the respiratory system [93]. application of the GABAA receptor antagonist picrotoxin paradoxically retains its excitatory responses [94]. ADEFS+ . cleft palate has been reported with GAD67 knockout mice [86]. childhood Infantile. 5. Using a conditionally expressed loss of function mutation of the γ2 GABAA receptor subunit in mice. A small subset of patients manifests epilepsy secondary to an autoimmune response against GAD65/67. Disrupting CCC Function May Predispose to Seizures Decreased expression or function of chloride extruders may change seizure susceptibility by not only diminishing the efficacy of GABAA inhibition and promoting cellular swelling and degeneration under hypotonic conditions. mice ARX mutations CAE+ Febrile. mutations in co-factors that are necessary for GAD65 function have been linked with early life seizures. that generates the GABA reserve pools. as complete KCC2 knockout mice die postnatally from respiratory failure. Limbic seizures Early life epileptic encephalopathies (infantile spasms. KCC2a and KCC2b. There is currently no known human mutation of KCC2 associated with epilepsy. GABA-related mutations Species Epilepsy type GABAA receptor mutations GABRA1 GABRA6 GABRB3 GABRD GABRE Human Human Human Human Human Human. Although total GABA content in the brain may be normal or decreased in GAD65 knockout mice. SMEI. a GABAA receptor antagonist [61].

Although their effects are not restricted to GABAA signaling. spasticity and intellectual disability.Neural Plasticity Table 2: Phenotype of CCC mutations.e. due to interactions with dendritic cytoskeletal proteins [108] or with other modulators of neuronal activity (i. circling behavior. increased threshold to thermal stimulation Bartter’s syndrome Ref. early mortality Increased seizure susceptibility and anxiety Hyperexcitability Peripheral neuropathy. growth retardation. Altered CCCs may also affect brain development in a more subtle fashion. Ohtahara syndrome. circling behavior Deafness. 112–116] (reviewed in [117]). From various fronts evidence emerges that shifts in the timing of emergence of hyperpolarizing signaling may have significant impact on neuronal and brain development and connectivity. Abnormal cortical development and synaptic connectivity may predispose to seizures or cognitive impairment. either in the form of less potent hyperpolarizing GABAA receptor currents or shunting inhibition [107]. which could predispose a brain to epilepsy even if it does not directly cause seizures. Pharmacological inhibition of NKCC1 with bumetanide from embryonic day E15 to PN7 in otherwise normal mice disrupts cortical dendritic formation [74]. Precocious appearance of hyperpolarizing GABAA receptor signaling. seizures have been reported Deafness Deafness. However. idiopathic infantile epileptic dyskinetic encephalopathy. may also create an imbalance in excitation/inhibition. 6. the function of KCC2 is more complex. some of whom have seizures as well as developmental deficits. CCC KCC1 KCC2 Location Ubiquitous Brain Mutation Knockout KCC2a and KCC2b knockout KCC2b knockout Hypomorph Heterozygote KCC3a-c knockout Knockout NKCC1a knockout Species Mouse Mouse Neurological effect None seen Death at birth Seizures. liver Ubiquitous Mouse Mouse Human. which is both a predisposing factor and a common comorbidity of young patients with epilepsy [111]. 104] NKCC2 Kidney Knockout Human [105] indicative of a residual inhibitory capacity of KCC2. like agenesis of the corpus callosum [100]. heart. which is expressed in many tissues. X-linked mental retardation [63–66. have been reported in patients with hereditary motor sensory neuropathy. Mutations of the aristaless-related and X-linked homeobox gene ARX have attracted a lot of interest due to their linkage with early life catastrophic epileptic syndromes. 5 [92] [93] Brain Mouse [94] Brain Brain KCC3 KCC4 NKCC1 Ubiquitous Kidney. disrupts cortical morphogenesis. in certain cases they may show a predilection to preferentially impair GABAergic inhibition. X-linked myoclonic seizures. increasing extracellular potassium) [109] which need to be further analyzed as to their ability to influence the phenotype of these mice. Secondary Disruption of GABAergic Signaling in Risk Factors for Early Life Epilepsy Conditions that predispose to epilepsy. mouse Mouse Mouse [95] [96] [97– 100] [101] [102] Ubiquitous NKCC1a and NKCC1b knockout Mouse [103. ARX is a transcription factor that regulates the proliferation and . lungs. Loss of function mutations in KCC3.. low weight. such as infantile spasms. defective spermatogenesis. either by KCC2 overexpression [72] or via loss of NKCC1 activity [110]. genetic or acquired.

This appears to aid the survival and regeneration process. Seizures can have immediate effects on GABAA signaling. 66]. or neuropeptide Y positive interneurons but also of striatal cholinergic neurons [64. not only to better understand the pathophysiological mechanisms investigating these changes but also to best interpret their pathophysiological relevance for epileptogenesis and brain function. there is limited information as to the consequences of neuronal trauma upon the expression. or delayed. α5. appearing after the termination of seizures. during the ictal period. 137]. have also suggested the presence of depolarizing GABA [20. a rare chromosomal deletion. a shift to the immature pattern of high NKCC1/KCC2 ratio in the lesional site [129] as well as reduced γ2 subunit expression and sensitivity to α1 subunit agonists in adulthood was described [130. behavioral deficits and epileptogenesis) emphasizing the importance of deficient GABA inhibition for their pathogenesis [64. reducing therefore GABA release [126]. composition. Pathology and electrophysiological studies from human tissue specimens from patients with cortical dysplasias.6 Insufficient inhibition: Normal GABAergic cell loss GABA receptor loss Excitatory GABA Miswiring/ malformation Neural Plasticity have been proposed to preferentially impair the sodium channel activity of GABAergic interneurons. Traumatic brain injury in adults. including infantile spasms. migration of GABA. promoting the brain-derived neurotrophic factor(BDNF-) dependent neuronal survival and may resolve with time. Excessive GABA inhibition may trigger seizures by disinhibiting target cells. have recapitulated several phenotypes of infantile spasms and associated phenotype (cognitive. Defining the timing of these events is crucial. Genotype-phenotype correlation suggested that deletion of the GABAA receptor subunits is associated with more severe seizures. involves the loss of ubiquitin-protein ligase 3A (UBE3A). such as in axotomized neurons. and myoclonus whereas patients with UBE3A mutations had a milder phenotype [118]. 127. In such cases a combination of the above models may be applicable at different sites of the epileptogenic network rendering the pharmacological effect of a GABAergic agonist not completely predictable by a single model. may differ. calbindin. Aberrant reappearance of depolarizing EGABA and reduced GABAA ergic responses have been proposed to underlie the pathogenesis of seizures from cortical malformations. such as CCCs or regulatory kinases. shunting inhibition may explain situations where GABAergic drugs silence excessive excitatory network activity. and γ3 GABAA receptor subunits [118]. GABA inhibition can fail when GABA or GABAA receptor expression is low. The β3 subunit knockout mouse strain also develops a similar epilepsy phenotype [119]. Please note that the effects of dysregulated GABA signaling in more complex neuronal networks. 131]. reduced GABAA ergic IPSCs and impaired chloride extrusion were found in juvenile rats. In the neonatal freeze lesion model. Anti-NMDA autoantibodies detected in limbic encephalitis. In the rat model of cortical dysplasias induced by prenatal exposure to the 1-3-bis-chloroethyl-nitrosurea. that is. the observed changes are dynamic and evolving. causes a reversal of GABAA signaling and CCC expression profile to the immature pattern (more depolarizing GABA and dominant NKCC1 over KCC2 activity) [133–135]. atypical absences. In both scenarios. during recovery [135]. In the partially isolated undercut cortical model. a rare cause of refractory and frequent seizures [125]. More detailed studies are needed to determine the role of posttraumatic GABAA signaling changes for healing and regeneration in the developing brain as well as its impact on subsequent epileptogenesis and ensuing cognitive deficits. Seizures may interfere with the expression. Two recently published mouse models of ARX loss of function mutations. 117]. diminishing their activity [124]. Seizures Alter GABAA Signaling Seizures can affect almost every neurotransmitter system in the brain. have been speculated to selectively target the NMDA receptors of presynaptic GABAergic terminals. when GABA depolarizes neurons. in neurons with depolarizing GABAergic signaling. reduced sensitivity to GABA was also seen in adulthood [132]. Furthermore. Loss of function mutations of the voltage-sensitive sodium channel SCN1A gene is found in not only the severe myoclonic epilepsy of infancy (Dravet syndrome) but also in ADEFS+ syndrome [120–123]. The temporal . one of which specifically disrupted it in GABAergic interneurons destined to migrate to the neocortex. and subcellular distribution of GABAA receptors and their regulatory factors. Disinhibition Excessive inhibition: Hypersynchrony Figure 2: Schematic depiction of simple models through which dysregulation of GABAA receptor-mediated inhibition can increase the activity of neuronal networks. or when miswiring and mistargeting of synapses occur. and connectivity of GABAergic interneurons in developing animals. 66. physiology. but in certain patients there is a more extensive deletion of the 15q11-13 chromosomal locus that contains three GABAA subunits. especially in the presence of abnormal circuitry or with specific pathologies. or via excessive synchronization of the neurons in the epileptogenic focus. 128]. However. suggesting a possible correlation between impaired GABAergic inhibition and posttraumatic cortical excitability [136. potentially generating seizures. Angelman syndrome. SCN1A mutations 7. β3. Few studies have advocated against the use of GABA enhancing drugs and in favor of GABAA receptor inhibitors as interventions to improve cognitive outcomes [138]. that commonly predispose to early life seizures.

7. on the contrary. β3 increase compared to controls In adulthood: increased α1 expression. enhanced zolpidem sensitivity Decreased α1 and increased α4 expression in the hippocampus of epileptic versus non-epileptic rats [141. Failure of GABAA receptor-mediated inhibition during prolonged seizures may also occur due to a positive shift in EGABA either because of buildup of intracellular Cl− concentration. are more effective early at onset of seizures than later on. the age at first seizure. given the maturational changes that are ongoing. medications.2. γ2 subunits but not of δ . In experimental studies. On the other hand. early life seizures functionally disrupt the physiology of GABAA receptor system. γ2 subunits. are not affected [139]. when SE has been established [147. sex. as well as cell type and region-specific features may determine the end effects upon GABAA receptor subunits or the direction of GABAA receptor-mediated responses (Tables 3 and 4). like benzodiazepines or barbiturates. somatosensory cortex Hippocampus [140] Recurrent flurothyl seizures Flurothyl seizures PN1-5 PN6 or PN6-10 Decreased amplitude of GABAergic IPSCs Decreased numbers of α1-ir neurons At 3 weeks postictally: α1. may contribute . epigenetic factors. α5 increase (CA3 only). from intense GABAA receptor-mediated chloride inward pumping. GABA-acting drugs. In newborn rats. yet cell death becomes a progressively more prominent feature as the age at exposure to SE increases [155. The transience of the efficacy of GABAergic drugs has been attributed to either increase internalization of selective synaptic GABAA receptor subunits. even 3 episodes of status epilepticus (SE) do not injure GABAergic neurons [30].Neural Plasticity Table 3: Effects of early life seizures on GABAA receptors and currents in rats. Seizure model Age Region Ictal changes In vivo SE (Lithium-pilocarpine. reduced mIPSCs Effects on GABAA receptors Ref. In addition. α4. larger GABA current. continuous hippocampal stimulation) In vivo SE (lithium-pilocarpine) Reduced surface expression of β2/3. prolonged seizures can lead to interneuronal loss but such effects are age-specific. during the first week of life. due to increased NKCC1 activity or decreased KCC2-mediated Cl− efflux [149–151]. the type and severity of seizures. but also the cellular diversity of specific operant signaling systems further modify the final outcomes. These changes may be either compensatory attempts to repair or restore normal function or. or from impaired chloride extrusion mechanisms. 142] [143] Kainic acid SE PN9 Hippocampus [144] Lithium-pilocarpine PN10 Hippocampus (dentate gyrus) [145] Lithium-pilocarpine SE PN20 Hippocampus [146] evolution of these events is also particularly important in developing rats. biological factors such as sex. Internalization of β2/3. Loss of GABAergic interneurons is a hallmark pathology of focal epilepsies. such as of β2/3 and γ2. like the δ subunit.γ2 decrease. 7. 140]. etiology or model of seizures. Postictal Changes. extrasynaptically located subunits that mediate tonic GABA inhibition. α3 increase. α2. The urgency in treating early SE has long been recognized in the clinical literature. Age at the time of seizures. 7 PN30 Hippocampus [139] 4–7 week old Hippocampus After seizures Hippocampus. In contrast. Ictal Attenuation of GABAA Receptor-Mediated Inhibition. 148]. like mesial temporal sclerosis [152–157]. which mediate the effects of benzodiazepines and barbiturates [139.1. 158–160].

following brief recurrent kainic acid seizures or an hour of kainic acid SE. But what happens. Similarly. in which the physiology of GABAA receptor-mediated signaling has reached a relative steady state. but only in the epileptic animals [145. after early life seizures. GABAA receptor subunits [141–146] (Table 3). period) hyperpolarizing shift of EGABA to the postictal dysfunction. The sequential interaction between carbonic anhydrase/GABAA receptors/KCC2 may therefore increase extracellular K+ . Lithium-pilocarpine SE at PN10 increases α1 subunit expression in the dentate granule . with still depolarizing GABAergic responses. 164]. It may also occur because of effective replenishment of intracellular bicarbonate by carbonic anhydrase during intense GABAA receptor activation. may contribute to epileptogenesis. in the first 10 days of life. 3KA-SE caused a precocious emergence of mature. more α2/α3 subunits) on the third postictal week [144] that typically attributes slower IPSC kinetics and less sensitivity to benzodiazepines. Kainic acid SE at PN9 rats favors the preservation of the immature pattern of GABAA receptor complex (less α1. We found that 3KA-SE caused only a transient appearance of depolarizing GABAA receptor mediated responses in neurons that had already started to shift to mature and more hyperpolarizing EGABA . a decrease in α1 subunit is noted. increasing its capacity to export Cl− [171]. or sequelae of seizures. developmental research is further complicated by the evolving changes that normally occur during the period when brain matures[161]. Taking advantage from the earlier appearance of GABAA receptor currents in females than in males. 167– 170]. carbonic anhydrase inhibitors have been used in certain cases as anticonvulsant therapies [109. 162]. in contrast. decrease α1 expression and the amplitude of GABAA receptor-mediated IPSCs [141–143]. whether seizures might have different effects upon GABAA receptor-mediated signaling in neurons with depolarizing or hyperpolarizing GABAA receptor mediated responses at the time of seizures. which are attributed to altered CCC expression or activity [30]. and 6 (3KA-SE) in CA1 pyramidal neurons with depolarizing EGABA (i. female) at the time of seizures [30]. Brooks-Kayal’s group has demonstrated that age at onset of SE is key at defining the final composition of GABAA receptors and that this. in other words. Looking at longer-term outcomes of early life seizures. These changes were attributed to Kainic acid Rat Low Mice Mg2+ seizures PN5 Kainic Rat acid (male) PN4-6 Kainic Rat PN4-6 acid (female) Kainic Rat acid (male) PN5-7 Switch from hyperpolarizing [184] Hippocampus to depolarizing EGABA Bumetanide sensitive Hippocampus [150] increase in − [Cl ]i After seizures Increased KCC2. [185] (at least 4 days more postictally) hyperpolarizing EGABA No change in KCC2. This is believed to occur in humans as well [127. There is no systematic research study taking us step-by-step through all the complexity of seizure-induced postictal alterations in GABAA receptor physiology and any extrapolations should be cautiously done pending confirmation by actual experimentations. in male neurons. Neural Plasticity cells in adulthood. In support. Model Species Age at Region seizures Ictal changes PN6-7 Effects Ref. that enhances KCC2mediated K+ /Cl− efflux [109]. during adulthood. contributing perhaps to the ability of the neurons to stop seizures. but not all. increased Hippocampus NKCC1 activity. we compared the effects of 3 episodes of kainic acid SE elicited at PN4.. In contrast. at the time seizures occur. As a result EGABA becomes more negative.e. Seizures selectively interfere with the expression of certain. similar to what was previously described for the adult neurons.e. when neurons are already in an immature state and how does this impact epileptogenesis and functional outcomes? In the immediate postictal period.. a factor that promotes the generation of ictal events. Seizures in adult animals tend to increase the ratio of NKCC1 over KCC2 activity. The reports of untimely appearance of depolarizing GABAA receptor signaling in a subpopulation of subicular neurons from adult human epileptic resected temporal lobes have attracted a lot of interest as a possible mechanism of epileptogenicity and potential refractoriness to GABA-acting antiepileptics [163. in turn. hyperpolarizing responses. [185] (at least 4 days more postictally) depolarizing EGABA Increased Hippocampus surface (immediate expression of [171] postictal KCC2. In the longer run. which leads to a depolarization and to a consequent influx of Cl− . Interestingly. reverting to a more immature pattern of CCC balance that favors depolarizing EGABA [151. recurrent flurothylinduced seizures. KCC2 is reshuffled towards the plasma membrane. Depolarizing GABAA receptor signaling has been linked to a dominance of NKCC1 over KCC2 activity in certain neurons of the epileptic tissue. comorbidities. decreased Hippocampus NKCC1 activity. 146]. 166]. 165]. further changes in EGABA function occur. then. such as cognitive dysfunction or epileptogenesis.8 Table 4: Effects of Seizures on CCCs. male) or isoelectric/hyperpolarizing EGABA (i. if SE is induced at PN20. 5. In our lab. may control the effects of seizures on CCCs and the direction of GABAA receptor-mediated signaling. we were interested in determining whether the original EGABA . Unlike the adults. reconstitution of α1 subunit expression prevented the occurrence of spontaneous seizures [146.

At the anatomical and electrophysiological level. by increasing our knowledge about the specific changes that occur in GABAA receptor composition and pharmacology. 173]. As a result. However the exact mechanisms underlying this therapeutic effect are not yet known. their effects will be region and cell type specific. and how such interventions influence long-term outcomes in subjects who have already experienced seizures or have epilepsy. and function-related specificity. as well as the timing of administration. cell type. 191]. most importantly. 74]. and different stressors are among the factors that can alter GABAA receptor signaling. The maturation of GABAA receptor system occurs asynchronously across different neuronal types and brain regions. can influence its efficacy in suppressing seizures [96. for how long. We still need to better understand and. and regional. BDNF increases KCC2 in developing neurons but decreases it in mature neurons [172. Another dual regulator of CCCs and EGABA through development is the brainderived neurotrophic factor (BDNF) pathway. hormones. Similarly. sex. Abbreviations ADEFS+ : Autosomal dominant epilepsy with febrile seizures plus ADJME: Autosomal dominant juvenile myoclonic epilepsy ADNFLE: Autosomal dominant nocturnal frontal lobe epilepsy ARX: Aristaless-related X-linked homeobox gene BDNF: Brain-derived neurotrophic factor CAE: Childhood absence epilepsy GABA: Gamma aminobutyric acid GABR: GABAA receptor GAD: Glutamic acid decarboxylase IGE: Idiopathic generalized epilepsy IPSC: Inhibitory postsynaptic current 3KA-SE: 3 episodes of kainic acid SE at PN4. more studies need to be done to determine which seizure types are more likely to respond. The result will be a state of postictal confusion or more sustained cognitive or behavioral deficits [6]. They may also disrupt the basic neural processes of learning and cognitive processing that depend upon GABA neurotransmission. bumetanide treatment has shown benefit in five infants with autism [183]. including the depolarizing GABA. Indeed. 30. since early life seizures change the direction and strength of GABAA receptor-mediated inhibition. 8. The precocious termination of depolarizing GABAA signaling would be expected to deprive brain from its neurotrophic effects that are important for normal development [72. The idea of pharmacologically enhancing GABA inhibition to stop seizures by using NKCC1 inhibitors like bumetanide is under investigation as a rationally developed. as may occur in chronic use in patients with focal epilepsies [74]. The need for biomarkers of GABAA function is therefore a priority. such as long-term potentiation (LTP) [174–176]. Moreover. 3KA-SE-exposed pups develop learning and memory problems when they grow up (unpublished data). However. so as to preserve normal brain function and development. 31. concerns have been raised about potential adverse developmental effects on innocent bystander normal brain tissues. very targeted. may be important for this protection. and individualized therapies to enhance GABA inhibition and stop seizures. further confusing the interneuronal communication protocols. 9. it may be possible to design more selective and specific GABAA receptor agonists for the very young or epileptic brain that is refractory to the existing medications. Conclusion The study of GABA in seizure generation and consequences has become a very fruitful field not only by generating intriguing results but also by producing challenging new questions. Implications for Early Life Seizures and Their Treatment Human and experimental evidence indicates that similar to adults. so as to implement such rational therapies. smart intervention to overcome the barriers posed by the well-established molecular switch of GABAA receptor function [21]. aberrant preservation of depolarizing GABAA signaling may also be a feature of the medically refractory epileptogenic focus in early life epilepsies. 192–196]. At present we do not have any data to discuss the pathological features of the medically sensitive early life epilepsies. model-specific differences. one day. We have learned a number of mechanisms that compromise GABAA inhibition in the very young or epileptic brain. to design such specific. predisposing to seizures and the associated cognitive and neurodevelopmental deficits. However. Emerging evidence suggests that GABA-acting drugs. The opposite patterns of KCC2 regulation by BDNF in certain systems has been proposed to be due to trkB-mediated activation of different intracellular signaling cascades that regulate KCC2 expression [151].5. context.6 KCC: Potassium chloride cotransporter LTP: Long-term potentiation NKCC: Sodium potassium chloride cotransporter . predict which is the normal balance between excitation and inhibition with sufficient age. 186– 189] and a human case report [190]. Our results indicate that age-specific factors. Of interest. Beneficial effects have been shown in few animal models [21. the inability of the immature neurons to persistently exhibit depolarizing GABAA receptor-mediated responses after seizures could be a protective feature against the development of subsequent epilepsy [30]. or social interactions [177–182]. it might be feasible. rendering it almost a moving target [11. 9 when is the optimal time to administer. Undoubtedly. The biggest challenge will be however to predict the functional state of GABAA receptormediated inhibition at the target areas.Neural Plasticity altered expression and/or activity of KCC2 and NKCC1. which is also activated in certain seizure models.

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