The Glutamatergic Dysfunction Hypothesis

for Schizophrenia
Joseph T. Coyle, MD
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Schizophrenia is a syndrome, undoubtedly with multiple etiologies, that variably exhibits

several features including positive and negative symptoms, cognitive deficits, onset in
young adulthood, and deterioration from the previous level of function. This review will
examine the growing evidence that dysfunction of corticolimbic glutamatergic neurotrans-
mission may contribute to or account for the manifestations of schizophrenia. Glutamater-
gic neurons represent the primary excitatory afferent and efferent systems innervating the
cortex, limbic regions, and striatum. The postsynaptic actions of glutamate are mediated
by a family of glutamate-gated ion channels that permit the influx of sodium and calcium,
thereby depolarizing (exciting) neurons. One of these receptors, the Kmethyl-D-aspartate
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(NMDA) receptor, is the site of action of psychotomimetics such as phencyclidine and

related anesthetics, which can reproduce in normal individuals most of the symptomatic
features of schizophrenia. An endogenous antagonist at the NMDA receptor, Kacetyl-
aspatfyl glutamate, appears to have enhanced activity in the frontal cortex and hippo-
campal formation in persons with this disorder. Glutamatergic dysfunction may be particu-
larly relevant to those forms of schizophrenia in which negative symptoms, cognitive
deficits, and deterioration are prominent features. In supporl of this inference, clinical
studies have shown that drugs that enhance NMDA-receptor function reduce negative
symptoms and cognitive deficits in persons with chronic schizophrenia who are receiving
neuroleptics. Thus, dysfunction of glutamatergic neurotransmission represents an important
organizational focus for research on the complex manifestations of schizophrenia. (HARVARD
REV PSYCHIATRY1996;3:241-53.)

Schizophrenia is one of the most persistent, disabling,
and costly forms of mental illness. Overt psychotic symp-
From the Consolidated Department of Psychiatry, Harvard Medical
School, Boston, Mass.
The author is the recipient of a Senior NARSAD Award and
receives research funding from NIMH and NINDS.
Original manuscript received 28 July 1995, accepted for publication
15 September 1995; revised manuscript received 22 September
1995.
Reprint requests: Joseph T. Coyle, MD, McLean Hospital, 115 Mill
St., Belmont, M A 021 78.
Copyright 0 1996 by Harvard Medical School.
1067132291961$5.00 + 0 39/1/69598
toms typically commence during the second or third decade
of life (with earlier onset in males than in females),' often
after an unremarkable premorbid development.2 The causes
of schizophrenia are probably several and interactive, since
genetic factors, fetal insults, and viral infection have all
been implicated."' Although the outcome is somewhat vari-
able, the majority of affected individuals exhibit waxing and
waning of acute psychotic symptoms complicated by a pro-
gressive and enduring impairment in motivational, atten-
tional, affective, and social functions."-' Neuropsychological
studies also reveal deficits in working memory, thought
organization, and language usage.'-'' These deficits corre-
late with reductions in volume of corticolimbic structures of
the brain including the temporal cortex, amygdala, and
Whether schizophrenia, or its subtypes, is a
progressive disorder has been a topic of debate since the
time of Kraepelin.2 The early course of illness certainly
24 1

242 Coyle
TABLE 1. Glutamate Receptors
Receptor family Ligands Subunits
NMDA Glu, ASP, NMDA NR1, NR2A-D
KA Glu, KA GluR5-7, KA1-2
AMPA Glu, AMPA, &A GluR1-4
Metabotropic Glu, QA, L-APB mGluR1-6 (G-
protein)
NMDA, N-methybaspartate; KA,kainate; AMPA, a-amino-3-
hydroxy-5-methylisoxazole-4-propionic acid; Glu, glutamate; Asp, the mechanisms responsible for cognitive deficits, negative
aspartic acid; QA, quisqualate; L-APB, L-2-amino-4-phosphonobu- symptoms, and deterioration.
Harv Rev Psychiatry Downloaded from informahealthcare.com by University of Toronto on 11/28/14
tyric acid; mGZuR, metabotropic glutamate receptor.
shows progressively worsening symptoms.6s16Also, recent
studiesl'~ls have provided convincing evidence that inad-
equately treated psychosis is associated with a poorer out-
come, suggesting that psychosis may produce relatively
irreversible brain changes.
Any theory that could explain the pathophysiology of
schizophrenia, therefore, must take into account at least five
aspects of the disorder: positive symptoms, negative symp-
toms, cognitive deficits, onset of symptoms in young adult-
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hood, and deterioration from the previous level of function.
For over 20 years the major explanatory hypothesis for the
pathophysiology of schizophrenia has centered on the
mechanism of antipsychotic effects of neuroleptics in terms
of blocking D, dopamine r e ~ e p t o r s . ~ The
~ - ' ~"dopamine hy-
pothesis" maintains that the clinical potency of neuroleptics
correlates impressively with affinity of these drugs for the
D, receptors, and that stimulants, which enhance central
dopaminergic neurotransmission, can produce the positive
symptoms of schizophrenia such as delusions, hallucina-
tions, and thought disorder. Postmortem as well as in vivo
imaging studie~'~-'~ have provided reasonably compelling
evidence that dysfunction of dopaminergic neurotransmis-
sion is an important element of the disorder. However,
although paradoxical dopaminergic hypofunction might con-
tribute to negative symptoms, dopaminergic dysfunction
would appear to account primarily for positive symp-
t o m ~ . ' ~ Furthermore,
.'~ the fact that neuroleptics may take
days to weeks to produce their full effect suggests that their
mechanism of action is indirect, requiring neuronal adapta-
tion beyond mere D, receptor blockade."' It is more difficult
to rationalize dopaminergic dysfunction as a complete ex-
planation of cognitive deficits, corticolimbic atrophy, and a
possible deteriorating course. With the advent of atypical
neuroleptics, especially clozapine, other neurotransmitter
systems such as the serotonin projections acting at 5-HT,
receptors have been implicated."
Recently, new insights into the pathophysiology of schizo-
phrenia have emerged from fundamental research into the
dual role of glutamate as the major excitatory neurotrans-
Harvard Rev Psychiatry
January/Februaty 1996
mitter in the brain and as the proximate cause of neuronal
degeneration, especially in disorders with symptomatic on-
set in adulthood or late This review will present the
evidence that the glutamatergic dysfunction can help to
explain the five aspects of schizophrenia described above
and leads to hypotheses that can be subjected to experimen-
tal validation. More important, if dysfunction of glutamater-
gic neurotransmission contributes to the pathophysiology of
schizophrenia, it offers possibilities €or therapeutic inter-
ventions that address not simply the positive symptoms but
GLUTAMATERGIC SYSTEMS
Quantitative brain morphometry, neuropsychological find-
ings, event-related potentials, and functional brain imaging
have all revealed both structural and functional abnormali-
ties in schizophrenia that affect diverse areas of the brain,
including the temporal cortex, hippocampus, anterior cingu-
late region, prefrontal area, amygdala, nucleus accumbens,
striatum, and t h a l a m u ~ . ~ ' -A~ common
~'~~ feature linking
the diverse brain structures affected in schizophrenia is the
excitatory neuronal system that interconnects them. Over
the last decade a compelling case has been made for the role
of glutamate (and related acidic amino acids) as the primary
excitatory neurotransmitter in the central nervous sys-
tem.34,35Specifically, the pyramidal cells of the cerebral
cortex, the granule cells of the hippocampus, and the exci-
tatory thalamocortical pathways appear to be glutamater-
g i ~The . ~ other
~ major neurotransmitter of the forebrain is
y-aminobutyric acid (GABA), which mediates inhibitory
neurotransmission. Whereas the glutamatergic neurons are
predominantly efferent, forebrain GABAergic systems (with
a few important exceptions such as the striatonigral path-
way) are primarily local circuit neu~ons.~' Thus, on the basis
of their anatomy alone, the glutamatergic neurons of the
forebrain would appear to be in a key position to play a
central role in the diverse pathology that characterizes
schizophrenia.
In concert with the delineation of the functional anatomy
of glutamatergic pathways has been the development of our
understanding of the receptors mediating glutamate's
physiological actions (see Table 1).On the basis of pharma-
cological and biophysical characteristics, three families of
glutamate-gated ion channels have been identified: N-me-
thyhaspartate (NMDA), kainic acid (KA),and cc-amino-3-
hydroxy-5-methylisoxazole-4-propionicacid (AMPA) recep-
t o r ~ AMPA. ~ ~ and KA receptors mediate fast excitatory
postsynaptic potentials, whereas NMDA receptors serve a
more modulatory function since they are recruited by depo-
l a r i z a t i ~ nThese
. ~ ~ glutamatergic-gated ion channels are the
dominant mediators of excitatory postsynaptic potentials
 Harvard Rev Psychiatry
Volume 3, Number 5
and also serve as important conduits for increasing intra-
cellular calcium. In addition, a family of glutamate receptors
linked to G protein-mediated intracellular responses has
been de~cribed.~'
The NMDA receptor (see Figure l), in particular, has
been extensively characterized with regard to the complex
modulatory sites of pharmacological imp~rt."~.""~' In ad-
dition to the recognition site for glutamate, there is a
second site to which glycine binds; occupation of the glycine
site is obligatory for glutamate-mediated channel opening.
D-Serine is another agonist at the glycine modulatory site,
and D-cycloserine,an antitubercular drug, serves as a partial
Harv Rev Psychiatry Downloaded from informahealthcare.com by University of Toronto on 11/28/14
agonist, activating it at low doses and inhibiting it at high
doses.'" Other modulatory sites include a binding site for
polyamines, a binding site for zinc, and a redox-sensitive
site. The NMDA-receptor channel is voltage dependent, with
magnesium occluding the channel at resting membrane
potential. Finally, there is a binding site within the channel
that becomes accessible, upon channel opening, to MK-801
and related drugs, phencyclidine (PCP), and ketamine,
which act as noncompetitive
Early studies of the biophysical characteristics of these
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glutamate-gated ion channelss4 indicated that the NMDA
receptor family conducted Na' as well as Ca2+ currents,
whereas the non-NMDA receptor channels sustained pri-
marily Na ' currents. The recent cloning of the genes en-
coding the polypeptides that form the various glutamate
receptors has revealed a higher level of molecular heteroge-
neity, pharmacological diversity, and biophysical variation.""
In particular, it is now known that posttranscriptional
messenger RNA (mRNA) editing transforms non-NMDA
receptors from permitting the passage of Ca2' to sustaining
only Na' currents.
With the availability of pharmacological tools to manipu-
late glutamate-receptor function, the role of these receptors
in mediating critical aspects of synaptic plasticity became
evident. Long-term potentiation (LTP), first characterized
in the hippocampus,'" causes a permanent increase in exci-
tatory synaptic efficacy as a consequence of a brief period of
high synaptic activity (for a review, see Kandel and
Schwartz""). Glutamate activation of non-NMDA receptors
mediates the excitatory postsynaptic potentials, but Ca2+
influx through NMDA receptors is primarily responsible for
the permanent change in synaptic efficacy," which may
involve feedback to the presynaptic glutamatergic terminals
by a diffusible second messenger such as nitric oxide. LTP is
now known to mediate glutamatergic synaptic plasticity in
many brain regions other than the hippocampus. LTP ap-
pears to be a critical element in the use-dependent synaptic
modification involved in memory and related cognitive func-
tions.4GGiven the fact that PCP blocks NMDA receptors, it
is not surprising that PCP both prevents LTP at a cellular
and disrupts cognitive functions in humans."
Coyle 243
AP-5
Gly, DCS I Glu, NMDA
n
l K + L l n
-
'I I
t '
Cat +
Na'
FIGURE 1. Schematic representation of the NMDA recep-
tor. The NMDA receptor is a glutamate-activated cation
channel, typically composed of two products - NR1 and
NR2A-D. Four sites of pharmacological relevance are
shown: (1) the glutamate (Glu) recognition site at which
NMDA can also serve as an agonist and aminophosphonova-
leric acid (AP-5)as an antagonist; (2) the glycine (G1y)-
modulating site, which must be occupied for glutamate to be
active b-cycloserine [DCS] is a partial agonist at this site);
(3) the binding site for phencyclidine (PCP) and its analogue
MK-801, which act as noncompetitive antagonists at the
open channel; and (4) a cation-binding site within the
channel, where magnesium (M$ ' ) acts as a voltage-depen-
dent antagonist.
KACENLASPARNL GLUTAMATE
An acidic dipeptide, N-acetylaspartyl glutamate (NAAG),
has been closely linked to glutamatergic neuronal systems.
Found in remarkably high concentrations (0.2-2.0 mmol/L)
in brain, NAAG has an uneven regional distribution there.
Immunocytochemical studies with highly specific polyclonal
and monoclonal antibodies against NAAG48.49 reveal colocali-
zation of NAAG in many putative glutamatergic neuronal
systems. Postmortem studies in humans5' reveal a subpopu-
lation of corticolimbic pyramidal neurons enriched with
NAAG. One well-characterized putative glutamatergic pro-
jection that contains high concentrations of NAAG is the
retinal ganglion cell-collicular pathway.51 Ca2+-dependent
release of endogenous NAAG from the collicular terminals
occurs as a consequence of stimulation of the optic nerve.52
NAAG is cleaved to N-acetyl aspartate (NAA)and glutamate
by a specific peptidase, N-acetylated a-linked acidic dipepti-
dase (NAALADase).NAALADase is a membrane-bound cell-
surface peptidase with high affinity for NAAG (Km = 100
nM). It is expressed in the brain, the kidneys, and the sexual
organs, like other peptidases involved in processing neu-

244 Coyle
ropeptides, and is regulated by persistent alterations in
excitatory n e u r o t r a n s m i ~ s i o n . ~The
~ - ~ gene
~ encoding for
NAALADase activity has been cloned.s6
The physiological actions of NAAG are complex. It is a
partial agonist at NMDA receptors and thus antagonizes
glutamate's activation of the NMDA r e ~ e p t o r . ~In ~ addition,
.~'
it activates a metabotropic glutamate receptor that inhibits
adenylate c y c l a ~ e .Through
~~ the action of NMLADase,
NAAG can also serve as a source of synaptic glutamate.
NAALADase activity is thus pivotal in determining whether
extracellular NAAG will remain intact, thereby inhibiting
NMDA receptors, or be converted to glutamate, thereby acti-
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vating the family of glutamate receptors. Consistent with
evidence of molecular heterogeneity of NMDA receptors,
NAAG has been shown to selectively block hippocampal LTP
of recurrent inhibition, which is mediated by NMDA recep-
tors on GAl3Aergic intraneurons.60
GLUTAMATE/DOPAMINE INTERACTIONS
The hypothesized dysfunction of glutamatergic neurotrans-
mission in schizophrenia interdigitates with the traditional
dopamine hypothesis of schizophrenia. Presynaptic D, re-
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ceptors on corticostriatal and limbic glutamatergic termi-
nals provide a negative regulation of glutamate release.6143
Neuroleptic blockade of these presynaptic receptors may
thereby enhance excitatory glutamatergic input to the cau-
date and putamen and to other forebrain regions receiving
dopaminergic innervation. However, neuroleptic interac-
tions in the cortex may alter glutamatergic function in
more-complex ways, as has recently been suggested by
Fitzgerald and colleague^.^^ They showed that chronic treat-
ment with haloperidol increased the amounts of the NMDA
receptor subunit NR1 expressed in the striatum and poste-
rior cingulate and of the AMPA receptor subunit GluRl in
the medial prefrontal cortex of the rat. These investigators
also observed a more regionally selective effect of chronic
clozapine treatment, with no alterations of NR1, GluR1, or
GluR2 in the striatum but significant elevations of GluRl in
the medial prefrontal cortex and of GluR2 in the frontal
cortex, parietal cortex, nucleus accumbens, and hippocam-
pus. Glutamatergic neurons have reciprocal interactions
with dopaminergic processes in their terminal fields.
M ~ g h a d d a mhas
~ ~ shown, for example, that glutamate as
well as dopamine release increases in prefrontal cortex as a
consequence of stress. Furthermore, the local pharmacologi-
cal blockade of AMPNKA receptors in prefrontal cortex
reduces the stress-induced increase in dopamine release,
strongly suggesting that glutamate modulates dopamine
release.66In addition, glutamate-dopamine interactions may
occur at the level of the individual n e ~ r o n . ~These
~ . ~ ' inter-
actions are consistent with the behavioral studies of Carls-
son and C a r l ~ s o nwhich
, ~ ~ showed that the locomotor effects
of apomorphine, a dopamine-receptor agonist, could be
markedly enhanced by cotreatment with the NMDA recep-
Harvard Rev Psychiatry
January/February 1996
tor antagonist MK-801,30and with the neurophysiological
interactions between dopaminergic and glutamatergic neu-
rotransmission reviewed by Grace.69
Evidence for glutamate/dopamine interactions has been
strengthened by studies of immediate early gene (IEG)
expression. IEGs are regulatory factors that alter neuronal
gene expression as a consequence of neurotransmitter-
receptor activation. Activation of NMDA receptors is a
potent stimulus for turning on IEG expression. Neurolep-
tics, D,-receptor antagonists, cause expression of IEGs in
the striatum, accumbens, and corticolimbic structures, pre-
sumably by disinhibiting glutamate release, although their
role in potentializing cyclic adenosine monophosphate by
blocking postsynaptic D, GI effects cannot be ex~luded.~"
The IEG response to neuroleptics is reversed by coadminis-
tration of NMDA-receptor antagonist^.^^ However, the
atypical neuroleptic clozapine affects IEG expression in
cortical and limbic regions but not in the s t r i a t ~ m . ~
Sys-
'
temic treatment of haloperidol-pretreated rats with D-cyclo-
serine, a partial agonist at the glycine-modulatory site on
the NMDA receptor, augments the IEG induction in the
s t r i a t ~ mThus,
. ~ ~ D-cycloserinebehaves like a neuroleptic in
this model, although it acts through the NMDA receptor
and not the dopamine D, receptor.
PSYCHOTOMIMETICS
Perhaps the most attractive argument implicating glutam-
atergic dysfunction in the pathophysiology of schizophrenia
involves the remarkable similarities in the symptomatic
manifestations of PCP-induced psychosis and schizophre-
nia. These similarities were noted over 20 years ago -before
there was any inkling about the mechanism of action of PCP
at the NMDA r e ~ e p t o r .Javitt
~ ~ . ~and
~ Zukin3' strengthened
the inferred relationship by showing that PCP psychosis
replicates not only the positive symptoms but also the
negative symptoms and cognitive deficits of schizophrenia.
Krystal and colleagues76performed a controlled study in
which the anesthetic ketamine, an analogue of PCP, was
administered to normal subjects to document its neuro-
psychiatric manifestations objectively. They noted that al-
though ketamine caused symptoms such as dissociation not
observed in schizophrenia, it also precipitated positive
symptoms, negative symptoms, and cognitive deficits in
normal subjects similar to those seen in individuals with
schizophrenia. The symptoms not associated with schizo-
phrenia may result from a diffuse inhibition of brain NMDA
receptors as a consequence of systemic treatment.
The virtual ubiquity of NMDA receptors in the brain4'
raises the question of how the 'activity of subsets of these
receptors might be selectively altered to yield the symptoms
of schizophrenia. The molecular identification of a family
of proteins (NR2A-D) that combine with the receptor-ion
channel (NR1) to form heteromeric NMDA receptors has
revealed a source of considerable variation in the phar-
 Harvard Rev Psychiatry
Volume 3, Number 5 Coyle 245

macological characteristics of these receptors:" Consistent
with this variation, Grunze and colleagues'" have found that
the NMDA receptors on the hippocampal GABAergic in-
terneurons are tenfold more sensitive to the synthetic
antagonist aminophosphonovaleric acid and the endogenous
antagonist NAAG than are NMDA receptors on hippo-
campal glutamatergic neurons.
In postmortem studies on the disposition of NAAG in
schizophrenia, Tsai and colleagues77 have found that
NAALADase, the enzyme responsible for cleaving NAAG to
NAA and glutamate,"J " is reduced in activity in the frontal
cortex, hippocampus, and parahippocampus in schizo-
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of sustaining glial cells but no change in neuronal cell
number. Rigorous cell-counting techniques have produced
only limited evidence of a reduction in neuronal number
in specific brain regions in schizophrenia."" Nevertheless,
several have indicated reductions in neuronal
number in regions including the mediodorsal nucleus
of the thalamus, the nucleus accumbens, the hippocampus,
and the cingulate area. Others, however, have reported no
loss of neurons in the hippocampu~"~ or the prefrontal
~~rte~.""~"~
One neuronal system that has figured prominently in the
postmortem studies comprises the GABAergic interneurons

phrenic subjects as compared to controls. Such a reduction
in NAALADase activity would prolong the synaptic effects
of NAAG, thereby favoring NMDA-receptor inhibition, es-
pecially on the GABAergic interneurons.
The role of inhibition of NMDA-receptor function in the
symptomatic manifestations of schizophrenia is also consis-
tent with the age of onset of symptoms. Children appear
much less vulnerable than adults to the psychotomimetic
effects of ketamine, compatible with an age of onset in early More recently, Akbarian and colleagues9" have reported a
ad~lthood.~"."" Benes"' has described the myelinization of
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of the cortical and limbic regions. Benes and colleagues""
found a significant reduction of the interneurons in layers 11,
111, V, and VI in the anterior cingulate area. Consistent with
this decline reflecting a loss of GABAergic neurons, the activ-
ity of glutamate decarboxylase and transport
sites for ['HIGABA are reducedg6in cortex while the density
of postsynaptic GABA, receptors is increa~ed,~'~"" as would be
expected for compensatory up-regulation of these receptors."
decrease in the mRNA encoding glutamate decarboxylase,

frontal glutamatergic pathways that occurs in late adoles- although they did not find a decrease in
cence. Perhaps this late myelinization (which permits the number of apparent GABAergic neurons in the cortex. In
glutamatergic functional input) and related structural aggregate, these results point to a reduction in the functional
changes provide the substrate for the psychotomimetic ef- influence of corticolimbic GABAergic interneurons, which
fects of noncompetitive NMDA-receptor antagonists and for inhibit the activity of glutamatergic efferent neurons.
the expression of idiopathic psychosis. Neuronal degeneration in the mature nervous system
is generally associated with an astrocytic response, thereby
NEURONAL LOSS indicating an area of recent or ongoing neuronal de-
generation. Well-controlled neuropathological studies in
The issue of neuronal loss in schizophrenia has confounded schizophrenia have been rather unrevealing or contradic-
investigators since schizophrenia was first des~ribed.".""."~ tory with regard to evidence of gliosis in the structures of
There are really two critical questions: is there a loss of interest."u37.100 These negative studies have lent support to
neurons in schizophrenia, and if so, when does it take place? the position that schizophrenia does not involve neuronal
With regard to the first question, quantitative morphomet- degeneration in the mature brain. However, apoptotic
ric StudieS1%.l:~.l.~.
s4 in recent years have provided compelling neuronal death (and not necrosis) could theoretically occur
evidence of volumetric reductions in cortical, limbic, and at the onset of acute symptoms, leaving little evidence of
midbrain structures in patients suffering from schizophre- reactive gliosis. This might account for the deterioration
nia. Inasmuch as the course and symptomatic characteris- occurring in the first 2 years after the initial episode."."
tics of the schizophrenia syndrome vary ~onsiderably,'~ re- Alternatively, hypoplasia (i.e., the failure to generate the
cent studies have increasingly focused on identifying corre- neurons during brain development) could account for a
lations between structural change in specific brain regions reduction in neuronal number that would not leave the
and such symptomatic manifestations as delusions, halluci- telltale signs of gliosis. Bloom1"' has reviewed the evidence
nations, and thought disorder.'".'" An overarching feature of that schizophrenia might involve a primary developmental
the quantitative morphometric studies is that volume re- defect in the central nervous system. It remains unclear
duction and enlargement of ventricles are greater in schizo- whether these second- to third-trimester correlates of im-
phrenic patients with poor outcome, more-prominent nega- paired brain maturation include a reduction in number of
tive symptoms, neuropsychological deficits, or tardive dys- neurons generated or are associated with a disproportionate
kineSia.S.26,S5.H6 amount of early apoptosis.
Reduction of brain volume is often but not invariably
associated with a decreased number of neurons. A notable GLUTAMATE AND NEURODEGENERATION
caveat comes from studies of the consequences of enriched
environments on rat c ~ r t e x , ~ ~which
.'' demonstrate an ex- Nearly a quarter of a century ago, Olney'n2 proposed the
pansion of the neuropil with increases in the number "excitotoxic hypothesis" to explain the selective pattern of

246 Coyle
neuronal degeneration that occurs as a consequence of acute
activation of glutamate-gated ion channels. Agonists at all
three subclasses of glutamate receptors cause perikaryal-
specific neuronal degeneration, although there is consider-
able variation in the vulnerability of neurons to the three
different receptor agonists.'03 This pattern of selectivity
mimics the specificity of neuronal vulnerability observed in
several neurodegenerative conditions including Hunting-
ton's disease, amyotrophic lateral sclerosis, spinocerebellar
degeneration, stroke, and t r a ~ m a . ~ ~These . ' ~ ~ similarities,
.'~~
along with findings from animal models, have provided
compelling circumstantial evidence that pre- or postsynaptic
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dysfunction of glutamatergic neurotransmission may be the
proximate cause of neuronal degeneration in such disorders.
Pioneering research by Choi and colleagues'o6 distin-
guished two forms of glutamate-induced neuronal degen-
eration. The first results from a massive influx of N a + ,
which causes the acute cellular edema observed by Olney
after systemic monosodium glutamate treatments. The
second is a delayed degeneration of neurons that is inde-
pendent of Na' but requires Ca2+.As reviewed by Coyle
and P~ttfarcken,"~oxidative damage appears to be an
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important mediator of the delayed degeneration resulting
from transient activation of NMDA and non-NMDA
receptors; evidence of this process is provided by elevated
levels of superoxide, membrane peroxidation, and protection
by agents that scavenge oxyradicals during the period of
damage.
Two separate mechanisms of cell death, consistent with
the existence of acute and delayed forms of glutamate
receptor-mediated neuronal degeneration, have recently at-
tracted considerable attention.'Os-lloThe first, necrosis, re-
sults typically from an external insult, is passive in nature,
is associated with the destruction of cellular integrity, and
often elicits an inflammatory response (reactive gliosis).The
second, apoptosis, is self-initiated, involves activation of
endonucleases, and often but not invariably requires de
novo protein synthesis. It is a mechanism involved in elimi-
nation of superfluous cells in development (such as occurs
with loss of trophic factors in the developing nervous sys-
tem) and may not elicit a persistent inflammatory cell
response. Recent evidence indicates that delayed neuronal
degeneration resulting from transient activation of non-
NMDA receptors exhibits many of the features of apoptotic
neurodegeneration."' Consistent with this, apoptosis often
involves oxidative damage as a mediator. (Bcl-2, for ex-
ample, an oncogene that prevents immune cell apoptosis,
exerts some of its protective effects by preventing oxidative
Thus, use-dependent glutamatergic mecha-
nisms may play an important role not only in neuroplastic-
ity but also in determining neuronal elimination.
In exploring the ability of noncompetitive NMDA-recep-
tor antagonists like MK-801 and PCP to block "excitotoxic"
lesions, Olney and c ~ l l e a g l l e s ' ~ discovered
~~"~ that these
"neuroprotective agents" cause a delayed degeneration of
Harvard Rev Psychiatry
January/February 1996
neurons in cortical and limbic regions. Pharmacological
studies'15 have indicated that this degeneration, pro-
voked by systemic treatment with NMDA-receptor antago-
nists, is mediated in part by non-NMDA receptors since
local injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-
quinoxaline prevents it. Furthermore, GABA-receptor ago-
nists (consistent with hypoactivity of GABAergic inter-
neurons in schizophrenia) and muscarinic acetylcholine-
receptor antagonists are also protective, implicating a
permissive role of these neurotransmitters. '16 Interestingly,
the corticolimbic neuronal degeneration induced by the
NMDA antagonists is preceded by the expression of heat
shock proteins, a marker associated with oxidative dam-
age,117and leaves minimal glial reaction, consistent with an
apoptotic form of death."'
Olney has developed an explanatory model for this
counterintuitive phenomenon: the activity of corticolimbic
GABAergic interneurons is particularly sensitive to NMDA-
receptor antagonists. Thus, PCP reduces the glutamatergic
activation of the GABAergic interneurons; the reduced
GABAergic tone, in consequence, disinhibits the corticolim-
bic glutamatergic neurons that they innervate. The en-
hanced glutamatergic efferent activity causes "excitotoxic
neuronal death" by persistent activation of non-NMDA
receptors on the postsynaptic neurons. Thus, interference
with NMDA receptor-driven activity of corticolimbic
GABAergic interneurons (or loss and/or impairment of
function of these interneurons) would favor a WAMPA
receptor-mediated delayed neuronal degeneration in animal
models. What further links this use-dependent neuronal
degeneration to schizophrenic psychosis is the observation
that both typical and atypical neuroleptics prevent the
neuronal
CLINICAL EVIDENCE OF NEURODEGENERATION
O'Donnell and colleagues'21 have observed a highly signifi-
cant increase in P300 latency as a function of age in persons
with schizophrenia but not in age-matched healthy controls.
The P300 is an electrical wave that can be detected in the
temporal lobe 300 milliseconds after an auditory stimulus.
Similar increases in P300 latency have also been observed in
other neurodegenerative disorders.122~123
NAA has been employed as a marker for neuronal integ-
rity in nuclear magnetic resonance (NMR) spectroscopic
studies. Immunocytochemical studies indicate that NAA is
highly localized to neurons;124its levels decline in animal
models of excitotoxin-inducedneuronal degenerati~nl'~ and
in postmortem studies of neurodegenerative disorders.lZ6
Using NMR spectroscopy, Yurgelun-Todd and colleague^'^^
found a significant reduction in the NAAIcreatine ratios in
the temporal cortex of persons with schizophrenia as com-
pared to suitable controls. That NAA decreases may repre-
sent a compromise of neuronal function and not simply
degeneration is supported by Meyerhoff and colleagues,
 Harvard Rev Psychiatry
Volume 3, Number 5
who used NMR spectroscopy to show that NAA is reduced in
patients with acquired immune deficiency syndrome (AIDS)
dementia, a condition not associated with marked neuronal
loss but with substantial inflammatory changes. This dis-
tinction may be important inasmuch as glutamate-mediated
use-dependent neuronal damage in schizophrenia is prob-
ably subtle and slowly progressive, with neuronal compro-
mise antedating apoptosis.
Consistent with an excessive activation of non-NMDA
receptors, which may be indicative of loss of neurons ex-
pressing these receptors, reductions in non-NMDA recep-
tors have been reported in certain cortical and limbic re-
Harv Rev Psychiatry Downloaded from informahealthcare.com by University of Toronto on 11/28/14
gions in postmortem studies in schizophrenia. In persons
with schizophrenia, a reduction in the specific binding of
["Hlkainate to its receptors has been described in the hip-
pocampal subfields including the area dentata and CA1, 2,
and 4,as well as in the parahippocampal gyrus; in contrast,
NMDA-inhibitable binding of [3H]glutamate has not been
found to be altered.'2y~'"'Concordant with these findings, a
reduction in the amount of mRNA for the non-NMDA
receptor gene (GluR K1) has been reported in the hippo-
campal formation, most notably in CA3 but also in CA1 and
For personal use only.
the subiculum.13' Other researchers have reported increased
["Hlkainate binding in the orbitofrontal cortex,'"2 medial
frontal cortex, and frontal eye field'33,134 in persons with
schizophrenia.
An aspect of schizophrenia that is consistent with the
hypothesis of an ongoing neurodegenerative process is the
vulnerability to tardive dyskinesia, a relatively irreversible
movement disorder. One of the most robust risk factors for
tardive dyskinesia is age.1s5.1'36 Prominent negative symp-
toms and evidence of organic changes in the brain are other
important predictors of increased vulnerability for tardive
dyskinesia in schizophrenic patient^.'^^,'^" There is an active
debate about the relative contribution of neuroleptic expo-
sure in the etiology of tardive dyskinesia. Reviews of case
records of schizophrenic patients hospitalized before the
advent of n e u r o l e p t i c ~ ' ~ ~indicate
~ ' ~ " that movement disor-
ders, including orofacial dyskinesias, were not uncommon.
Furthermore, current studies carried out in small numbers
of neuroleptic-naive schizophrenic patients in developing
countries indicate that tardive dyskinesia occurs in about
20% and first appears approximately a decade after the
onset of the p~ychosis.'~'
Brain imaging, postmortem human studies, and animal
models strongly suggest that tardive dyskinesia involves a
degeneration of striatal neurons, particularly GABAergic
efferent^.^^^.'^:' Although caudate volume has been reported
to increase with acute neuroleptic treatment, striatal vol-
ume is often reduced in patients with tardive d y s k i n e ~ i a . ' ~ ~l e a g u e ~ ' ~have
Removal of dopaminergic innervation to the striatum, a
functional consequence of neuroleptic treatment, causes
apoptotic neuronal death in the rat ~ t r i a t u m . 'Since~ ~ oxi-
dative damage is an important component of apoptotic
neuronal degeneration and neuroleptics increase striatal
Coyle 247
glutamatergic input,"3 it is not surprising that reduced
activity of superoxide dismutase in cerebrospinal fluid, in-
creased markers for glutamatergic neurotransmission, and
elevated oxidized proteins distinguish schizophrenic pa-
tients who have tardive dyskinesia from those who do not.'46
These findings are consistent with studies indicating that
vitamin E, a free radical scavenger, decreases the symptoms
of tardive dyskinesia.'47.'4h
NMDA-RECEPTOR ACTIVATION IN SCHIZOPHRENIA
The most salient prediction from the hypothesis of NMDA-
receptor hypofunction as a component of schizophrenia is
that agents that enhance activation of NMDA receptors
should reduce symptoms in schizophrenia. Insofar as posi-
tive symptoms, negative symptoms, and cognitive impair-
ments are caused by NMDA-receptor antagonists, they
should all be responsive to NMDA-receptor agonists. How-
ever, NMDA-receptor agonists, as treatments, bear signif-
icant risks -convulsions and NMDA receptor-mediated
neuronal degeneration.'4y Therefore, researchers consider-
ing a possible pharmacological strategy selected D-cyclo-
serine (DCS) since it is a partial agonist at the glycine
modulatory site on the NMDA r e ~ e p t o r ~ ' .and ' ~ ~crosses
~~~'
the blood-brain bar~-ier.'~".'~~ Thus, it enhances the response
of the NMDA receptor to endogenous glutamate without
directly activating the Furthermore, as a partial
agonist, DCS actually impairs NMDA-receptor activation at
high doses, thereby limiting neurotoxic and convulsant
effect~.~l.l~~
In a double-blind, placebo-controlled dose-finding
on a cohort of patients with chronic schizophrenia who had
prominent negative symptoms and were receiving neurolep-
tics, 50 mg of DCS produced a significant reduction in
negative symptoms and significantly enhanced performance
on a frontal lobe-dependent cognitive task. However, nei-
ther 15 nor 250 mg of DCS improved symptoms, thereby
yielding a U-shaped dose response consistent with the com-
pound's partial agonist properties. In support of the lack of
efficacy of high-dose DCS, Cascella and c o l l e a g ~ e s have
'~~
reported that 250 mg of DCS caused a deterioration in
patients with schizophrenia. In vivo studies in rats similarly
demonstrated that 1 mg/kg (nearly equivalent to 50 mg in
an adult human-i.e., 0.7 mg/kg) enhanced the IEG re-
sponse to haloperidol, whereas 5 mgkg (nearly equivalent to
250 mg in an adult human) attenuated this response.73
Thus, the U-shaped dose-response curve for DCS observed
at the receptor level and in vivo in rats was replicated in the
schizophrenic patients. Independently, Javitt and col-
" demonstrated that treatment with glycine
itself also significantly reduces the negative symptoms in
persons with schizophrenia. Since patients in both of these
studies were already receiving neuroleptics, the effects of
glycine modulatory site agonists on positive symptoms re-
main to be determined.

248 Coyle
GABA-Rc V
KA-Rc l_r
Q
Glutamate
Y reduced ability to synthesize GABA, alone or in combination,
Harv Rev Psychiatry Downloaded from informahealthcare.com by University of Toronto on 11/28/14
Neuroleptics
FIGURE 2. Schematic representation of hypothesized dys-
functional glutamatergic circuits in corticolimbic structures
in schizophrenia. NMDA receptors on local circuit GABA-
ergic neurons are differentially sensitive to antagonism by
phencyclidine (PCP) and related drugs, as well as to endog-
enous N-acetylaspartyl glutamate (NAAG). The consequent
decreased local inhibition of corticolimbic glutamatergic ef-
ferents results in excessive activation of their postsynaptic
neurons via non-NMDA kainate (KA) receptors. Persistent
For personal use only.
activation of the KA receptors may lead to apoptotic degen-
eration of these neurons. DA, Dopamine; 5-HT serotonin.
CONCLUSIONS
The findings reviewed above can be integrated into the syn-
aptic model of schizophrenia presented in Figure 2. The
NMDA-receptor antagonists such as PCP and ketamine re-
produce the positive, negative, and cognitive symptoms of
schizophrenia in normal subjects, primarily through their
action at NMDA receptors on GABAergic interneurons in
cortical and limbic regions. The consequent hypofunction of
these GABAergic neurons would increase the excitability of
projecting glutamatergic efferents from the regions. As a con-
sequence, the affected cortical areas would have a decreased
ability to filter or restrict incoming excitatory input, resulting
in a spread of extraneous information. Regionally selective
impairments in the inhibitory regulation of afferent and ef-
ferent excitatory neurotransmission could account for such
symptoms of schizophrenia as hallucinations, delusions, and
thought disorders. Reduced activity of NAALADase, observed
in the frontal cortex, hippocampus, and parahippocampus in
postmortem studies in schizophrenia, could produce an ana-
tomically circumscribed "PCP-like" effect by favoring the
maintenance of synaptic NAAG, which selectively antago-
nizes the NMDA receptors on the GABAergic interneurons.
Although this scenario is plausible and internally consis-
tent, alternative findings have been reported. Nevertheless,
much of the postmortem research supports an operational
hypofunction of the GABAergic interneurons. For example,
Benes and colleague^^^,^^ have developed circumstantial evi-
dence that there is a loss of GABAergic neurons in specific
layers of the anterior cingulate cortex (i.e., reduced numbers
Harvard Rev Psychiatry
January/February 1996
of interneurons, decreased glutamate decarboxylase activ-
ity," and an inferred up-regulation of GABAA receptors).
Although Akbarian and c011eagues~~ could not confirm a re-
duction in the number of GABAergic interneurons, they did
find a significant decrease in the amount of mRNA encoding
glutamate decarboxylase,the enzyme responsible for the syn-
thesis of GABA. Inasmuch as the causes of schizophrenia are
undoubtedly heterogeneous, it is not surprising that the find-
ings on the specifics of GABAergic dysfunction are not uni-
form. Nevertheless, reduced excitatory drive through the ac-
tion of NAAG, reduced number of GABAergic neurons, and
would impair the inhibitory control over corticolimbic
glutamatergic efferents. Conversely, pharmacological inter-
ventions that presynaptically enhance GABAergic function
should have therapeutic effects.
An important consequence of disinhibition of corticolim-
bic glutamatergic efferents is excessive stimulation of
glutamate receptors on postsynaptic neurons. Persistent
activation of non-NMDA glutamate receptors can produce a
delayed degeneration of neurons, with cytopathological fea-
tures of apoptosis- a form of neuronal death not associated
with an inflammatory glial reaction. This form of neuronal
death is consistent with the reported absence of gliosis in
schizophrenic Indeed, systemic treatment with
PCP and related noncompetitive NMDA-receptor antago-
nists causes a delayed neuronal degeneration in cortical and
limbic regions, with features of apoptosis.
Whether neuronal death occurs in the mature brain in
schizophrenia- either at the time of symptomatic onset
and/or as an ongoing process - remains a subject of debate.
Decreases in brain levels of NAA, a marker of neuronal
integrity, have been described in schizophrenia from NMR
spectroscopic studie~,"~ and an age-related prolongation of
event-related potentials, similar to that observed in well-
characterized neurodegenerative disorders, occurs in schizo-
phrenia."l Inadequate treatment early in the course of
schizophrenia is associated with poorer long-term outcome,
suggestive of a degenerative pro~ess.'~ Tardive dyskinesia
might also be a manifestation of a latent neurodegenerative
process in schizophrenia, with the threshold for manifesta-
tion of symptoms lowered by neuroleptic treatment. Anti-
oxidants reduce the symptoms of tardive dyskinesia, consis-
tent with an apoptotic form of neuronal death.'47.'48How-
ever, against this evidence for neuronal loss must be
considered a series of studies in which careful quantitation
has not revealed a reduction in neuronal number.
Perhaps one way of rationalizing the contradictory find-
ings in the neuropathology of schizophrenia is to recognize
the heterogeneity of the causes and the course of the
disorder. Crow5 addressed this heterogeneity by proposing
two different forms of the disorder: type I, with little evidence
of structural change in the brain and a predominance of
positive symptoms, and type 11, with obvious structural brain
atrophy and prominent negative symptoms. The risk for tar-
 Harvard Rev Psychiatry
Volume 3, Number 5
dive dyskinesia is greater in patients with brain atrophy.
Although more-recent studies do not support such a simple
dichotomy, the model proposed in this review would more
likely be applicable to patients showing loss of corticolimbic
volume, poor response to neuroleptic treatment, negative
symptoms, and cognitive impairments. Consistent with this
hypothesis, patients selected on the basis of preexisting
negative symptoms while being treated with neuroleptics
exhibited a reduction in negative symptoms and improve-
ment in cognitive function when treated with DCS, a partial
agonist at the glycine modulatory site on the NMDA
receptor."" In a group of schizophrenic patients who were
Harv Rev Psychiatry Downloaded from informahealthcare.com by University of Toronto on 11/28/14
receiving neuroleptics but were not selected for nega-
tive symptoms, glycine loading also decreased negative
symptoms.'58
Many issues remain unresolved with regard to the
hypothesis of glutamatergic dysfunction in schizophrenia.
First, if the hypothesis is correct, then enhanced NMDA-
receptor function should also reduce positive symptoms.
This might be accomplished with minimal risk of extrapy-
ramidal side effects. Second, the therapeutic effects of DCS
and glycine on negative symptoms suggest that a n un-
For personal use only.
foreseen action of clozapine may be enhancement of NMDA-
receptor function. If this is the case, then DCS would
probably not have additive effects with clozapine. To the
contrary, as a partial agonist, DCS and related drugs might
attenuate the therapeutic effects of clozapine on negative
symptoms. Third, clinical experience with neuroleptics and
especially clozapine suggest that the full effects may not be
evident during the initial weeks of treatment. Given the role
of the NMDA receptor in long-term potentiation and syn-
aptic remodeling, it is possible that the therapeutic effects
of enhancers of NMDA function might increase with time
and might potentiate the impact of psychotherapeutic and
rehabilitative interventions. Finally, most potent psycho-
tropic medications bear the risk of significant side-effects.
Since the NMDA receptor is involved in neuronal excitation
and neurodegenera- tion, the risks for seizures and neuronal
loss must be carefully assessed in clinical trials to enhance
NMDA-receptor function.
The excellent secretarial assistance of Frances MacNeil and
helpful discussions with Drs. Benes, McCarley, Goff, Renshaw, and
Cohen are gratefully acknowledged.
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