Download cortical inhibitory neurons and schizophrenia

REVIEWS
CORTICAL INHIBITORY NEURONS
AND SCHIZOPHRENIA
David A. Lewis*‡, Takanori Hashimoto* and David W. Volk*
Abstract | Impairments in certain cognitive functions, such as working memory, are core features
of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB
neurotrophin receptor leads to reduced GABA (γ-aminobutyric acid) synthesis in the
parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal
cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory
responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a
diminished capacity for the gamma-frequency synchronized neuronal activity that is required for
working memory function. These findings reveal specific targets for therapeutic interventions to
improve cognitive function in individuals with schizophrenia.
PSYCHOSIS
This refers to distortions in
inferential thinking, such as
delusions (fixed, false beliefs that
are firmly held in the face of
contradictory evidence), and
perceptual disturbances, such as
hallucinations. Auditory
hallucinations, usually
experienced as voices distinct
from one’s own thoughts, are
most common in schizophrenia.
Departments of *Psychiatry
and ‡Neuroscience,
University of Pittsburgh,
Pittsburgh, Pennsylvania
15213, USA.
Correspondence to D.A.L.
e-mail: [email protected]
doi:10.1038/nrn1648
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| APRIL 2005 | VOLUME 6
Schizophrenia is a devastating illness that affects
approximately 1% of the world’s population1. Affected
individuals frequently come to clinical attention during
late adolescence or early adulthood, about 10% will
eventually commit suicide and most experience a lifetime of disability. As a result, schizophrenia is associated
with a substantial emotional burden for the families of
those affected and it incurs tremendous economic costs
for society in terms of medical expenditure and lost
productivity.
The risk of developing schizophrenia is directly
proportional to the degree of genetic relatedness to an
affected individual2, and several putative susceptibility
genes for schizophrenia have been identified3. However,
the degree of risk conferred by each gene seems to be
small, and, for most genes, the biological basis of the
increased risk for illness remains unclear. Furthermore,
the degree of concordance for schizophrenia among individuals with the same genetic make-up is only about
50% (REF. 2), which indicates that genetic liability alone
might not be sufficient to cause the clinical features of
the illness. Consistent with this interpretation, various
environmental events across development, from advanced paternal age at the time of conception to frequent
cannabis use during adolescence, seem to increase the
likelihood of developing schizophrenia later in life4.
Therefore, the etiology of schizophrenia is thought to
require an interaction between genetic susceptibility
and environmental risk factors, which alters neurodevelopmental processes that occur before the onset of
the diagnostic features of the illness.
Although PSYCHOSIS is usually the presenting and most
striking clinical aspect of schizophrenia, it is not diagnostic of the disorder. Schizophrenia is recognized by the
presence of impairments in social and occupational
functioning (BOX 1) that result from the confluence of a
range of disturbances in brain function, including abnormalities in perception, inferential thinking, fluency and
production of language, expression of emotion, capacity
for pleasure, volition and attention5.
Of the many clinical features of schizophrenia, disturbances in certain cognitive processes, such as impairments in attention, memory and executive functions
(that is, the ability to plan, initiate and regulate goaldirected behaviour), might represent the core features of
the illness6. Cognitive abnormalities have been found
throughout the life span of individuals with schizophrenia, including during childhood and adolescence7,
and at the initial onset of psychosis8. The unaffected relatives of individuals with schizophrenia also show similar,
although milder, cognitive deficits9, which indicates that
the cognitive deficits are not caused by treatment with
antipsychotic medications or the chronic nature of the
illness. The cognitive disturbances of schizophrenia have
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Box 1 | Diagnostic criteria for schizophrenia
At present, no findings from laboratory procedures, neuroimaging methods or
psychological tests are diagnostic of schizophrenia. Schizophrenia is diagnosed on the
basis of the clinical syndrome, that is, the clustered appearance of a characteristic set of
signs and symptoms. For the purpose of diagnostic reliability, these features have been
formulated into specific criteria5. The first diagnostic criterion requires the presence of two
or more of the following clinical features: delusions, hallucinations, disorganized thinking
(as reflected by tangential or incoherent speech), grossly disorganized or catatonic
behaviour, and negative symptoms. The latter include altered emotional expression (for
example, flat affect), poverty of speech (for example, alogia) and avolition (for example,
the inability to initiate and persist in goal-directed activities). The second diagnostic
criterion requires evidence of social or occupational dysfunction, such as deterioration in
interpersonal relationships, work habits or personal hygiene, from the level achieved prior
to the appearance of the clinical features. Third, the signs of the disturbance must be
continuously present for at least six months. Fourth, it must be clear that the clinical
features are not attributable to another disorder, including substance abuse.Although
establishing the validity of these criteria remains an ongoing area of investigation, the
application of these criteria is very reliable, which results in a high degree of concordance
across research clinicians in the diagnosis of schizophrenia.At present, available
treatments for schizophrenia are primarily effective in suppressing the psychotic features
of the illness; they have limited impact on negative symptoms, and do not appreciably
improve the social or occupational outcome for most individuals.
WORKING MEMORY
The active maintenance of
limited amounts of information
for a short period of time to
guide thought processes or
sequences of behaviour.
Working memory is typically
assessed through delayed
response tasks in which a
stimulus cue is briefly presented
and removed, a delay period
ensues, and then a response is
required based on information
contained in the stimulus cue.
a greater negative impact on daily activities than do the
psychotic symptoms, and the degree of cognitive dysfunction might be the best predictor of long-term functional outcome for individuals with schizophrenia10.
Despite the clinical importance of these cognitive
abnormalities, there are no approved pharmacological
treatments for these deficits. Furthermore, all medical
treatments currently used for schizophrenia, which primarily suppress the psychotic features, were discovered by
chance. The development of more effective treatments,
and possibly of secondary prevention measures, requires
greater knowledge of the underlying disease process
(FIG. 1). Specifically, how do complex and variable combinations of genetic liabilities, environmental risk factors
and developmental processes alter the structure and function of the brain and produce the characteristic clinical
symptoms of schizophrenia? Typically, the starting point
Pathogenesis
(reduced signalling
through TrkB)
Etiology
Pathophysiology
(reduced gamma
band power)
Pathological entity
(deficit in chandelier
cell-mediated inhibition)
Prevention
Clinical syndrome
(impaired working
memory)
Treatment
(GABAA α2 agonist)
Figure 1 | Components of the disease process of schizophrenia. The cluster of clinical signs
and symptoms (clinical syndrome) characteristic of a brain disorder, such as schizophrenia, is the
result of some cause or set of causes (etiology). The cause or causes induce the disease
mechanisms (pathogenesis), which produce abnormalities in the brain (pathological entity) that
alter its function (pathophysiology). The development of effective treatments or preventative
measures requires the ability to interrupt or reverse the pathophysiological processes and
pathogenetic mechanisms, respectively. For each component of the disease process of
schizophrenia, the data reviewed in this article provide convergent evidence for the indicated
abnormalities. TrkB, tyrosine kinase Trk (tropomyosin-related kinase) receptor B.
NATURE REVIEWS | NEUROSCIENCE
for addressing this question is the clinico-pathological
correlation — the identification of a pathological entity
that is associated with the clinical syndrome. An important challenge in schizophrenia research has been to
identify a pathological entity that is associated with the
core cognitive deficits of the illness.
In this review, we illustrate one strategy for characterizing the components of the disease process of schizophrenia, beginning with the cognitive features of the
clinical syndrome. Specifically, we review evidence that
certain cognitive abnormalities in schizophrenia reflect
pathology in specific cortical inhibitory circuits; that
these pathological alterations might arise from specific
pathogenetic mechanisms; and that these pathological
alterations result in pathophysiological processes that
have implications for new therapeutic interventions. As
such, this article is not intended to provide a comprehensive review of the abnormalities found in inhibitory
neurons in individuals with schizophrenia, which have
been reviewed elsewhere11,12.
Working memory deficits in schizophrenia
Certain crucial cognitive deficits in schizophrenia seem
to reflect alterations in executive control, which includes
context representation and maintenance functions, such
as WORKING MEMORY, that depend on the DORSOLATERAL
13
PREFRONTAL CORTEX (DLPFC) . Individuals with schizophrenia tend to perform poorly on working memory
tasks and to show reduced DLPFC activation when
attempting to carry out such tasks14,15. In addition, under
conditions in which individuals with schizophrenia perform normally on working memory tasks, activity in the
DLPFC can be increased, which indicates that the DLPFC
operates less efficiently16.
Several findings support the relevance of these alterations in DLPFC function to the disease process of
schizophrenia. First, individuals with other psychotic
disorders17 or major depression18 show normal activation
of the DLPFC when carrying out working memory
tasks, which indicates that the abnormalities observed in
schizophrenia are, at least in part, specific to the clinical
syndrome of schizophrenia. Second, the severity of
deficits in activation of the DLPFC, but not of other
cortical regions, during working memory tasks predict
the severity of cognitive disorganization symptoms in
individuals with schizophrenia15. Third, it has been suggested that reduced working memory capacity might be
rate limiting in the performance of other cognitive tasks
in schizophrenia19. Therefore, working memory deficits
seem to be a central feature of schizophrenia, and identifying the pathological entity (or entities) in the DLPFC
that produces these functional alterations is essential for
understanding the underlying disease process.
A pathological entity in schizophrenia
Working memory and inhibition in the DLPFC.
Although working memory is an emergent property of
a neuronal network that is distributed across a number
of brain regions20, it depends on the coordinated and
sustained firing of subsets of DLPFC PYRAMIDAL NEURONS
between the temporary presentation of a stimulus cue
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mechanism for the disturbances in working memory in
individuals with schizophrenia. Consistent with this
view, tissue concentrations of the mRNA that encodes
the 67 kiloDalton isoform of glutamic acid decarboxylase (GAD67), an enzyme that synthesizes GABA, are
reduced in the DLPFC of individuals with schizophrenia26–31. Indeed, reduced GAD67 mRNA expression
in the DLPFC is one of the most consistent findings in
postmortem studies of individuals with schizophrenia32.
The deficit in GAD67 mRNA seems to be accompanied
by a corresponding decrease in the cognate protein,
although this has been less extensively studied28. By
contrast, mRNA and protein levels of GAD65, another
enzyme that synthesizes GABA, are not altered in the
DLPFC of people with schizophrenia28, and the density
of GAD65-immunoreactive axon terminals also remains
unchanged33. Interestingly, elimination of the Gad65
gene in mice does not alter cortical levels of GABA34,
whereas reductions in GAD67 mRNA are associated
with marked decreases in cortical GAD activity and
GABA content35.
CRC
1
DB
2
DB
G
3
WA
ais
Ch
Ng
4
5
M
6
Grey matter
White matter
Figure 2 | Morphological and biochemical features of subpopulations of cortical GABA
neurons in the dorsolateral prefrontal cortex. The diagram illustrates the calcium-binding
proteins — parvalbumin (blue), calbindin (red) and calretinin (yellow) — and the locations of inhibitory
synaptic inputs to a pyramidal neuron (green) by different morphological classes of cortical GABA
(γ-aminobutyric acid) neurons. The chandelier (Ch) and wide arbor (WA) or basket neurons provide
inhibitory input to the axon initial segment (ais) and the cell body proximal dendrites, respectively, of
pyramidal neurons. By contrast, the calbindin-expressing double bouquet (red DB), neurogliaform
(Ng) and Martinotti (M) neurons tend to provide inhibitory inputs to the distal dendrites of pyramidal
neurons. Finally, calretinin-expressing (yellow) DB and Cajal–Retzius cell (CRC) appear to target both
pyramidal cell distal dendrites and other GABA (G) neurons. 1–6, layers of dorsolateral prefrontal
cortex. Modified, with permission, from REF. 41  (1994) John Wiley & Sons, Inc.
DORSOLATERAL PREFRONTAL
CORTEX
(DLPFC). Those regions on the
dorsal surface of the primate
frontal lobe that are located
rostral to the motor and premotor
regions, and which include
Brodmann’s areas 9 and 46.
PYRAMIDAL NEURONS
These constitute ~75% of
cortical neurons, and are
recognized by their triangular
cell bodies, a single apical
dendrite directed toward the
cortical surface and an array of
basilar dendrites. The dendrites
of these neurons are studded
with many spines, and their
axons project into the white
matter and provide excitatory
projections to other cortical
regions or subcortical structures.
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and the later initiation of a behavioural response21.
Although other neurotransmitter systems are also
involved, DLPFC neurons that use the inhibitory neurotransmitter GABA (γ-aminobutyric acid) seem to be
crucial for such synchronization of pyramidal neuron
activity during working memory processes. For example,
fast-spiking GABA NEURONS in the monkey DLPFC are
active during the delay period of working memory
tasks22, and are necessary for task-related neuronal firing
and the spatial tuning of neuronal responses during
working memory 23. In addition, the injection of GABA
antagonists into the DLPFC disrupts working memory24.
Constantinidis and colleagues25 suggested that during
working memory tasks inhibition might serve both a
spatial role (controlling which DLPFC pyramidal
neurons are activated during working memory) and a
temporal role (controlling when they are active during
the different phases of working memory).
These findings indicate that impairments in GABAmediated inhibition in the DLPFC could provide a
Gene expression deficits in a subset of GABA neurons.
Cortical GABA neurons are heterogeneous, with various
subpopulations that can be distinguished by a combination of morphological, physiological and molecular
attributes (FIG. 2). Distinct subpopulations of GABA
neurons seem to have specialized functions in regulating
pyramidal neuron activity36,37. For example, the chandelier (or axo–axonic) subpopulation of GABA neurons
express the calcium-binding protein parvalbumin38, have
a fast-spiking, non-adapting firing pattern39 and project
a linear array of axon terminals (termed cartridges)
that synapse exclusively on the axon initial segments of
pyramidal neurons40 (FIG. 3a,b).
Wide arbor (basket) cells in the monkey DLPFC also
express parvalbumin41 and have fast-spiking electrophysiological features that are indistinguishable from
those of chandelier neurons42. However, the axons of
wide arbor neurons have a much larger spread than those
of chandelier cells, and their axon terminals mainly target
the cell bodies and proximal dendrites of pyramidal
neurons38. The proximity of the perisomatic inhibitory
synapses — formed by parvalbumin-expressing chandelier and wide arbor neurons — to the site of action
potential generation in pyramidal neurons indicates that
these GABA neurons might be specialized to regulate the
output of pyramidal neurons.
The calcium-binding protein calbindin is expressed in
double bouquet, neurogliaform and Martinotti cells,
which are not fast-spiking and provide axon terminals
that synapse on the distal dendrites of pyramidal cells43,44.
Finally, ~50% of GABA neurons in the monkey DLPFC,
many of which are double bouquet cells, express the
calcium-binding protein calretinin41, have a regularspiking, adaptive firing pattern39,44 and produce axon
terminals that target distal dendritic spines or shafts on
pyramidal cells or other GABA neurons45. So, the functional consequences of a deficit in GAD67 in schizophrenia depend on whether all or a specific subpopulation
(or subpopulations) of GABA neurons are affected.
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a
b
neuron correlated strongly with the change in density of
GAD67 mRNA-positive neurons. These findings indicate
that GAD67 mRNA expression was markedly reduced in
parvalbumin-expressing neurons that also had reduced,
but still detectable, levels of parvalbumin mRNA. This
was confirmed by dual label in situ hybridization studies,
which revealed that ~50% of parvalbumin mRNApositive neurons lacked detectable levels of GAD67
mRNA in individuals with schizophrenia47. These
findings are consistent with immunocytochemical
studies that failed to find a reduction in the densities of
parvalbumin-positive neurons in the DLPFC of individuals with schizophrenia48,49. So, it seems that the
number of parvalbumin-expressing GABA neurons are
not reduced in the DLPFC of individuals with schizophrenia, but that they have decreased expression of
several important genes and might, therefore, be
functionally impaired.
c
10 µm
Figure 3 | Pre- and postsynaptic markers of chandelier neuron inputs to the axon
initial segment of pyramidal neurons. a,b | Immunoreactivity for GABA (γ-aminobutyric
acid) transporter 1 (GAT1; a) and parvalbumin (b) clearly identifies vertical arrays of chandelier
neuron axon terminals (cartridges) that are located below the cell bodies of unlabelled
pyramidal neurons. c | Immunoreactivity for the α2 subunit of the GABAA (GABA type A)
receptor is localized postsynaptically, in the axon initial segment of pyramidal neurons.
Modified, with permission, from REF. 116 © (2003) John Wiley & Sons, Inc.
GABA NEURONS
These comprise ~25% of
cortical neurons, have smooth
or sparsely spiny dendrites and
provide axons that project
locally within the cortical grey
matter.
Studies of GAD67 mRNA expression at the cellular
level showed that, in individuals with schizophrenia, the
density of neurons with detectable levels of GAD67
mRNA was significantly decreased in DLPFC layers 3–5,
but not in layer 6 (REFS 26,27). Furthermore, in neurons
with detectable levels of GAD67 mRNA, the expression
level per neuron did not differ from control values27.
These observations indicate that in individuals with
schizophrenia, most DLPFC GABA neurons express
normal levels of GAD67mRNA. However, ~25–30% of
GABA neurons do not express this transcript at a detectable level. In the same cohort of individuals, expression
of the GABA membrane transporter 1 (GAT1) — a
protein responsible for reuptake of released GABA into
nerve terminals — was also decreased, with almost identical cellular patterns46. Therefore, in schizophrenia, both
the synthesis and reuptake of GABA seem to be greatly
reduced in a subset of DLPFC inhibitory neurons.
Recent evidence indicates that the affected GABA
neurons include those that contain the calcium-binding
protein parvalbumin, which is present in ~25% of
GABA neurons in the primate DLPFC41. In individuals
with schizophrenia, the expression of parvalbumin
mRNA was shown to be significantly decreased in layers
3 and 4, but not in layers 2, 5 or 6, of the DLPFC47 (FIG. 4).
However, in contrast to the findings for GAD67 and
GAT1 mRNAs, the density of neurons with detectable
levels of parvalbumin mRNA was unchanged in individuals with schizophrenia, although the expression level
per neuron was significantly decreased. In the same individuals, the parvalbumin mRNA expression level per
NATURE REVIEWS | NEUROSCIENCE
Alterations in chandelier neurons. In addition to the
unique role of parvalbumin-expressing GABA neurons
in regulating pyramidal cell activity, their distinctive
developmental trajectories in the monkey DLFPC,
especially during adolescence (BOX 2), indicate that alterations in these neurons might contribute to working
memory dysfunction in schizophrenia. Consistent with
this hypothesis, the density of chandelier neuron axon
cartridges that were immunoreactive for GAT1 was
significantly reduced in the DLPFC of individuals with
schizophrenia50 (FIG. 5), with the most extensive reduction seen in the middle cortical layers51. By contrast,
immunoreactivity of GAT1 in other axon terminal
populations was unchanged50. Together with the gene
expression studies reviewed above, these findings indicate that chandelier neurons in the DLPFC of individuals
with schizophrenia express decreased levels of parvalbumin mRNA and undetectable levels of GAD67 and
GAT1 mRNAs, the latter of which results in reduced
GAT1 protein in their axon cartridges.
Despite the convergence of these findings for a common GABA-containing cell type, it is unclear how GABA
neurotransmission at the synapse between the chandelier
neuron and the pyramidal cell axon initial segment is
altered in schizophrenia. These findings could reflect
deficient inhibition, resulting from a primary reduction
in GABA synthesis, or excessive inhibition, secondary to
a reduction in GABA reuptake. To distinguish between
these alternatives, it might be useful to analyse GABAA
(GABA type A) receptors on the postsynaptic targets of
chandelier neuron axons.
GABAA receptors are pentameric hetero-oligomers
that are composed of subunits from seven different
classes, several of which have more than one member.
For example, most GABAA receptors in the cortex contain one of six α subunits that have different subcellular
distributions and physiological properties52. Although
present in only ~15% of cortical GABAA receptors53, the
α2 subunit is found at >95% of inhibitory synapses
onto pyramidal neuron axon initial segments54 (FIG. 3c),
especially in the superficial layers of the human cerebral
cortex55. In addition, GABAA receptors that have the α2
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a
b
120
PV mRNA
100
80
3
60
nCi/g
1
2
4
Control
Schizophrenia
‡
*
40
5/6
20
White matter
0
1
2
3
4
5/6
4
5/6
Cortical Layer
Low density
High density
120
CR mRNA
100
80
3
60
4
nCi/g
1
2
Control
Schizophrenia
40
5/6
20
White matter
1 mm
0
1
2
3
Cortical Layer
Figure 4 | Expression of parvalbumin and calretinin mRNAs in the dorsolateral prefrontal cortex. a | Pseudocoloured
autoradiograms showing the different laminar distribution patterns of the GABA (γ-aminobutyric acid) neurons that express parvalbumin
(PV) or calretinin (CR) mRNAs in the dorsolateral prefrontal cortex of human control subjects. b | The bar graphs show the mean (SD)
expression level of each transcript, by cortical layer, in individuals with schizophrenia and matched control subjects. The expression of
parvalbumin mRNA is significantly decreased in layers 3–4 of individuals with schizophrenia, whereas the expression of calretinin mRNA
is unchanged across all layers. nCi/g, nanoCuries/gram; 1–6, layers of dorsolateral prefrontal cortex. *P = 0.012, ‡P = 0.005. Modified,
with permission, from REF. 47 © (2003) Society for Neuroscience.
subunit seem to have a higher affinity for GABA, which
results in faster activation and slower deactivation times
than GABAA receptors that have the more common α1
subunit56,57. So, GABAA receptors that have the α2 subunit seem to be anatomically located and functionally
specialized to mediate a potent inhibitory influence on
the output of pyramidal neurons.
In the DLPFC of individuals with schizophrenia, the
density of pyramidal neuron axon initial segments that
are immunoreactive for the GABAA α2 subunit is
increased by >100% compared with control subjects58
(FIG. 5). This seems to reflect higher levels of α2 subunits
at the axon initial segment rather than an increase in the
density of pyramidal neurons59 or of their axon initial
segments60. Furthermore, the density of α2-immunoreactive axon initial segments was inversely correlated
with the density of GAT1-immunoreactive cartridges
in the same individuals with schizophrenia (FIG. 5). So, in
the DLPFC of individuals with schizophrenia, GABAA
receptors seem to be upregulated at pyramidal neuron
axon initial segments in response to deficient GABA
release from chandelier axon terminals. Furthermore, as
changes in GAD are not seen in mice that lack GAT1
(REF 61), both the increase in postsynaptic GABAA receptors and the decrease in presynaptic GAT1 are likely to
be compensatory responses to a more primary deficit in
GAD67 mRNA expression.
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Although they are more difficult to assess, similar preand postsynaptic changes might also occur in the inputs
of parvalbumin-expressing wide arbor neurons to the
perisomatic region of pyramidal neurons. For example,
the density of parvalbumin-immunoreactive puncta —
possibly the axon terminals of wide arbor neurons62 — is
reduced in the middle but not the superficial layers of
the DLPFC in individuals with schizophrenia63, which
parallels the laminar pattern of decreased expression of
parvalbumin mRNA in schizophrenia (FIG. 4). Furthermore, the increased density of GABAA receptors in the
DLPFC of individuals with schizophrenia in ligand binding studies64,65 was most prominent at pyramidal neuron
cell bodies65. These data indicate that, in schizophrenia,
GABAA receptors at the soma and axon initial segments
of pyramidal neurons might be locally upregulated in
response to a reduction in perisomatic inhibitory input
from chandelier and wide arbor neurons (FIG. 6).
Given the restricted locations of these synaptic alterations, and the fact that inhibitory inputs to the cell bodies
and axon initial segments of pyramidal neurons represent
<10% of the total complement of inhibitory synapses
on the cell, it is not surprising that changes in the mRNA
levels of the main postsynaptic GABAA receptor subunits
have not been detected in the DLPFC of individuals with
schizophrenia66. However, some studies have reported
increases in the mRNA for the α1 subunit67,68.
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Box 2 | Postnatal development of chandelier neuron inputs
Specificity to the disease process of schizophrenia.
Whether these findings represent a clinically relevant
pathological entity in schizophrenia depends, in part, on
the extent to which they are specific to the disease
process of schizophrenia. In this regard, neither parallel
studies in individuals with other psychiatric disorders
(FIG. 5), nor studies in monkeys that were chronically
exposed to antipsychotic medications in a fashion that
mimics the clinical treatment of schizophrenia, replicated
the alterations in markers of GABA neurotransmission
that are described above27,46,47,51,58.
Furthermore, these deficits seem to be relatively
specific to parvalbumin neurons and are not found in
many other GABA neurons in the DLPFC in individuals
with schizophrenia. For example, most GABA neurons
in the DLPFC express normal levels of GAD67 and
GAT1 mRNAs27,46. Moreover, the expression of calretinin mRNA, which is found in about half of the GABA
neurons in the primate DLPFC41, is also unchanged in
individuals with schizophrenia47 (FIG. 4), as is the density
of calretinin-immunoreactive puncta, which presumably
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PV varicosity number per 400 µm2
Cartridge and ais number per mm2
The axon terminals of chandelier
Birth
3m
15 m 42 m
Adult
20
350
neurons are vertical arrays of boutons
(cartridges) that are immunoreactive
for parvalbumin (PV) or GABA
300
membrane transporter 1 (GAT1), and
outline the axon initial segment of
15
pyramidal neurons (FIG. 3a,b).
PV
250
varicosities
Although the developmental time
course differs somewhat for these two
P
markers, as illustrated in the diagram,
200
the density of labelled cartridges is low
GABAA
10
PV
α2 ais
in the DLPFC of newborn monkeys,
cartridges
150
increases to reach a peak before the
GAT1
cartridges
onset of puberty, and then declines
markedly during adolescence (shaded
100
area between 15 and 42 months of age)
5
to adult levels116. These density
changes in parvalbumin- and GAT50
immunoreactive cartridges seem to
reflect developmental shifts in the
concentration of these proteins (and
0
0
so in the detectability of cartridges) as
0.01
0.1
1
10
100
1,000
Log age (months)
cartridges are readily visualized with
the Golgi technique over this same
time period117. Interestingly, the peak and subsequent decline in the density of labelled cartridges occurs prior to the age at
which the peak density of parvalbumin-immunoreactive varicosities — putative axon terminals from the wide arbor class
of parvalbumin-expressing GABA (γ-aminobutyric acid) neurons (FIG. 2) — is achieved62. Postsynaptically, the
detectability of the α2 subunit of the GABAA (GABA type A) receptor in pyramidal neuron axon initial segment is high at
birth, and then markedly declines during adolescence before stable adult levels are achieved.
The marked developmental changes in these pre- and postsynaptic markers of inhibition at the inputs from chandelier
and wide arbor cells to the perisomatic region of pyramidal neurons indicate that the capacity to synchronize pyramidal
neuron output in the DLPFC might be in substantial flux until adulthood. Consequently, the protracted developmental
time course of improvements in performance on working memory tasks118 might depend on both refinements in the
number of excitatory connections among pyramidal neurons and changes in their proximal inhibitory inputs (for a
review, see REF. 119). These developmental changes during adolescence might contribute to unmasking the consequences of
inherited abnormalities in the regulation of GABA mediated neurotransmission and might help to explain why certain life
experiences during adolescence (for example, stress or cannabis exposure) seem to increase the risk for schizophrenia4.
Panel adapted, with permission, from REF. 116  (2003) John Wiley & Sons, Inc.
represent a substantial proportion of GABA axon terminals48. However, abnormalities in parvalbumin neurons
alone might not completely account for the deficits in
expression of GAD67 and GAT1 mRNAs, as such
changes were also observed in cortical layers 1 and 2,
where relatively few parvalbumin-expressing GABA
neurons are located41, and where no changes in the
expression of parvalbumin mRNA were found47 (FIG. 4).
Regional specificity. Are these abnormalities in GABA
neurotransmission restricted to the DLPFC, or do they
represent a disturbance that is distributed across other
cortical regions that might contribute to other aspects
of the clinical syndrome of schizophrenia? Initial
studies of the hippocampus reported a decrease in the
density of non-pyramidal, putative GABA neurons69
and an increase in GABAA receptor binding 69 in schizophrenia. However, a recent study from the same research
group did not detect a difference in the expression of
either GAD67 or GAD65 mRNAs in the hippocampus
of individuals with schizophrenia, although both
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150
Schizophrenia
Major depression
Change from matched
control group (%)
100
50
0
–50
GAT1 cartridge
α2-ais
–100
Figure 5 | Changes in pre- and postsynaptic markers of
GABA input to the axon initial segment of pyramidal
neurons in the dorsolateral prefrontal cortex of
individuals with schizophrenia. The bar graph shows the
mean percentage change in the densities of GABA
(γ-aminobutyric acid) transporter 1 (GAT1)-immunoreactive
cartridges and GABAA (GABA type A) receptor α2 subunit
immunoreactive axon initial segments (ais) in the dorsolateral
prefrontal cortex of individuals with schizophrenia or major
depressive disorder compared with matched control subjects.
Note that the changes of these markers in schizophrenia are
reciprocal and seem to be disease-specific. Modified, with
permission, from REF. 58  (2002) Oxford University Press.
transcripts were decreased in individuals with bipolar
disorder70. In the anterior cingulate cortex of individuals with schizophrenia, the densities of non-pyramidal
neurons69 and of neurons that were immunoreactive for
the calcium-binding protein calbindin71 were reported
to be reduced in layer 2, as was the density of GAD67
mRNA-positive neurons72. In the superior temporal
gyrus, the level of GAD67 mRNA was reduced67, as was
the density of GAT1-immunoreactive axon cartridges,
although to a lesser extent than in the DLPFC of the same
individuals with schizophrenia73. So, although the current
knowledge base is not sufficient to provide a definitive
answer, the available data indicate that changes in GABA
neurotransmission in schizophrenia might be a common feature of neocortical regions, but not of the hippocampus70, and that the magnitude of these changes
might be larger in the DLPFC than in other neocortical
regions.
Uncovering a pathogenetic mechanism
REELIN
Reelin is a large protein that is
secreted into the extracellular
matrix by Cajal–Retzius cells.
It regulates the migration of
cortical neurons during
development. The absence of
reelin in the reeler mouse results
in a distinctive alteration of the
normal cellular architecture of
the cortex.
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| APRIL 2005 | VOLUME 6
The importance of the changes in parvalbumin-expressing GABA neurons as a pathological entity in schizophrenia would be strengthened by showing that they co-occur
in the illness with abnormalities that represent potential
pathogenetic mechanisms, and by confirming in animal
models that these correlations represent cause and effect.
In this section, we review the evidence for several pathogenetic mechanisms that could produce such changes in
GABA neurons in the DLPFC.
Reduced levels of reelin. Reductions in mRNA and protein levels for REELIN, in association with deficits in the
expression of GAD67 mRNA, have been reported in the
DLPFC and several other brain regions in individuals
with schizophrenia67. However, in contrast to control
subjects, the levels of reelin and GAD67 mRNAs were not
correlated in individuals with schizophrenia28. Reelin is
expressed in ~50% of GABA neurons in the adult rodent
cortex74, and heterozygote reeler mice (expressing 50% of
the normal levels of reelin) show decreased GAD67
mRNA expression75. However, reelin is apparently not
expressed in parvalbumin-expressing cortical GABA
neurons76; therefore, the relationship between decreased
reelin expression and the preferential reduction of GAD67
mRNA expression in parvalbumin-positive neurons in
individuals with schizophrenia requires further study.
Reduced excitatory drive. It has been suggested that the
deficit in GAD67 mRNA expression represents an activity-dependent change in response to reduced activity of
excitatory circuits in the DLPFC26. One source of such
excitatory inputs is the mediodorsal nucleus of the thalamus, which is the principal source of thalamic projections to the DLPFC. Interestingly, initial studies reported
that the number of neurons in this nucleus was reduced
in individuals with schizophrenia; however, recent studies
have not confirmed these observations (for a review, see
REF. 77). Furthermore, experimental reductions in neuron
number in the mediodorsal thalamus of rodents did not
change the expression of GAD67 mRNA in the prefrontal
cortex78. However, other changes, such as a decreased
density of dendritic spines (a marker of excitatory synaptic inputs to pyramidal neurons) in the DLPFC of
individuals with schizophrenia79,80, are consistent with
reduced excitatory drive in DLPFC circuits, although the
source of these altered inputs has yet to be determined. In
addition, convergent lines of evidence indicate that
schizophrenia might be associated with reduced neurotransmission through NMDA (N-methyl-D-aspartate)
glutamate receptors81 and, interestingly, the administration of NMDA receptor antagonists to rodents reduces
parvalbumin levels in cortical GABA neurons82.
One potential source of such altered excitatory inputs
is the hippocampus. Various structural and functional
abnormalities have been observed in the hippocampi of
individuals with schizophrenia, and some of these seem
to be correlated with alterations in the DLPFC. For
example, Weinberger and colleagues observed that tissue
levels of N-acetyl-aspartate, a putative marker of neuronal integrity, were decreased in the hippocampus and
DLPFC, but not in other brain regions, of individuals
with schizophrenia83. To explore this association, they
used a rodent model in which lesions of the ventral
hippocampus are created neonatally 84. In adulthood,
these animals, in addition to mimicking a number of
other phenotypic features of schizophrenia, show deficits
in GAD67 expression in the prefrontal cortex85. However, whether the deficits in GAD67 mRNA expression
show the cell type specificity, and are accompanied by
the other changes in GABA markers that are present in
schizophrenia, has not yet been investigated.
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REVIEWS
1
2
GAD67
GAT1
CR
mRNAs
3
GAT1 IR
4
GABAA α2 IR
5
6
GAD67
GAT1
PV
mRNAs
Grey matter
White matter
Figure 6 | Schematic summary of alterations in GABA circuitry in the dorsolateral prefrontal cortex of individuals with
schizophrenia. Reduced levels of gene expression in chandelier neurons (blue) are associated with a decrease in immunoreactivity
(IR) for GABA (γ-aminobutyric acid) transporter 1 (GAT1) in the axon cartridges of these neurons and an upregulation of GABAA
(GABA type A) receptor α2 subunit immunoreactivity in the postsynaptic axon initial segment of pyramidal neurons (green). Gene
expression in calretinin (CR)-expressing subpopulations of GABA neurons does not seem to be altered (yellow). GAD67, 67 kD
isoform of glutamic acid decarboxylase; PV, parvalbumin; 1–6, layers of dorsolateral prefrontal cortex.
Variants in the GAD67 gene. Recently, allelic variants in
the GAD67 gene have been reported to be associated
with an increased risk for schizophrenia86. Whether and
how these variants would result in cell-type specific
changes in GAD67 mRNA expression are unknown.
Reduced neurotrophin signalling. Signalling by brainderived neurotrophic factor (BDNF) through its receptor,
the tyrosine kinase Trk (tropomyosin-related kinase) B
receptor (TrkB), promotes the development of GABA
neurons and induces the expression of GABA-related
proteins, including GAD67, GAT1 and parvalbumin87,88.
These effects might be selective for parvalbumin-expressing cortical GABA neurons, as TrkB is predominantly
expressed by GABA neurons that express parvalbumin,
but not by those that express calretinin89. So, reduced
BDNF–TrkB signalling might contribute to the altered
expression of GABA-related genes in the DLPFC of individuals with schizophrenia. Consistent with this hypothesis, the mRNA and protein levels for both BDNF and
TrkB have been found to be reduced in the DLPFC of
individuals with schizophrenia31,90 (FIG. 7), and the expression of these mRNAs seems to decrease early in the course
NATURE REVIEWS | NEUROSCIENCE
of the illness. Comparisons with the results of other
studies indicate that, in individuals with schizophrenia,
the decreased tissue levels of these mRNAs represent
changes in gene expression rather than a loss of DLPFC
neurons91. In contrast to BDNF and TrkB, the mRNA
expression of TrkC — the receptor tyrosine kinase for
neurotrophin 3 — is unchanged31.
The changes in the expression levels of TrkB and
GAD67 mRNA were strongly correlated (r = 0.74,
P < 0.001) in the same individuals, and this correlation
was significantly stronger than that between BDNF and
GAD67 mRNAs, indicating that changes in TrkB expression might be a pathogenetic mechanism that results in a
reduction in GABA-related gene expression in individuals
with schizophrenia. However, these correlations in human
studies do not show a causal relationship. Consequently,
as a proof of concept test that reduced signalling through
TrkB receptors could cause changes in expression of
GABA-related genes in schizophrenia, we used TrkB
hypomorphic mice in which the insertion of floxed TrkB
cDNA (fBZ) resulted in decreased TrkB expression92.
Compared with wild-type mice, expression levels of TrkB
mRNA in the prefrontal cortex were significantly
VOLUME 6 | APRIL 2005 | 3 1 9
REVIEWS
nCi/g
140
Schizophrenia
Control
BDNF mRNA % control
394
201
143
107
82
61
25
100
80
60
40
20
0
BDNF mRNA
0
nCi/g
F 1,23 = 18.8
P < 0.001
120
C
140
F 1,24 = 22.4
P < 0.001
TrkB mRNA % control
741
509
397
336
210
129
68
nCi/g
100
80
60
40
20
C
140
GAD67 mRNA % control
3,470
1540
1120
810
550
320
110
GAD67 mRNA
0
120
0
TrkB mRNA
0
100
80
60
40
20
C
140
PV mRNA %control
860
620
390
210
90
0
0
PV mRNA
1 mm
1 mm
S
F 1,12 = 10.8
P = 0.006
2,080
1,200
S
F 1,24 = 19.4
P < 0.001
120
0
nCi/g
S
120
100
80
60
40
20
0
C
S
Figure 7 | Reduced neurotrophin and GABA-related gene expression in the dorsolateral prefrontal cortex of individuals
with schizophrenia. The autoradiograms show the laminar distribution of brain-derived neurotrophic factor (BDNF), tyrosine kinase
Trk (tropomyosin-related kinase) receptor B (TrkB), 67 kD isoform of glutamic acid decarboxylase, (GAD67) and parvalbumin (PV)
mRNAs in the dorsolateral prefrontal cortex of a control individual and the reduced levels of these transcripts in a matched individual
with schizophrenia. The densities of hybridization signals are presented in pseudocolours according to the calibration scales for each
mRNA. Solid and broken lines indicate the pial surface and the border between the grey and white matter, respectively. The bar graphs
show the mean (SD) expression of each transcript in individuals with schizophrenia (S) and matched control subjects (C). F, Fisher’s
F distribution resulting from the analyses of variance; the subscript numbers indicate the corresponding degrees of freedom. nCi/g,
nanoCuries/gram. Modifed, with permission, from REF. 31  (2005) Society for Neuroscience.
decreased by 42% and 75% in fBZ/+ and fBZ/fBZ mice,
respectively; and in fBZ/fBZ mice, the expression levels of
GAD67 and parvalbumin mRNAs in the prefrontal
cortex were significantly decreased by 25% and 40%,
respectively31 (FIG. 8). In addition, in the fBZ/+ mice, the
expression levels of GAD67 and parvalbumin mRNAs
were intermediate between the wild-type and fBZ/fBZ
mice. The cellular pattern of reduced GAD67 mRNA
expression in these mice also precisely paralleled that seen
in individuals with schizophrenia27. That is, the density of
neurons with detectable levels of GAD67 mRNA was significantly reduced, but the expression level of GAD67
mRNA per neuron was unchanged31. Furthermore, consistent with the selective vulnerability of a GABA neuron
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| APRIL 2005 | VOLUME 6
subpopulation in schizophrenia, the TrkB genotype did
not affect the expression of calretinin mRNA. So, the
changes in the expression of GABA-related genes in TrkB
hypomorphic mice replicate those found in individuals
with schizophrenia at both the tissue and cellular levels.
By contrast, although the expression of BDNF mRNA
was decreased by 80% in the prefrontal cortex of mice
with a neuron-specific inducible knockout of Bdnf 93,
there were no changes in the expression levels of GAD67
or parvalbumin mRNAs in these animals, whether the
Bdnf knockout was induced during embryogenesis or in
adulthood31. These findings indicate that changes in TrkB
but not BDNF expression regulate the expression of
GABA-related genes in the prefrontal cortex.
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REVIEWS
nCi/g
6,840
Wild Type
fBZ/+
140
fBZ/fBZ
120
TrkB mRNA
% wild type
2,840
1,400
850
550
TrkB mRNA
60
40
140
4,890
120
GAD67 mRNA
% wild type
2,560
1,540
970
590
270
GAD67 mRNA
F 2,6 = 11.1, P = 0.010
a
b
b
100
80
60
40
20
0
nCi/g
140
3,070
120
PV mRNA
% wild type
1,580
980
650
410
190
0
80
0
nCi/g
0
100
20
260
0
F 2,6 = 51.1, P < 0.001
a
c
b
1 mm
PV mRNA
F 2,6 = 9.92, P = 0.013
a
ab
b
WT
fBZ/+
fBZ/fBZ
100
80
60
40
20
0
Figure 8 | Changes in gene expression in the prefrontal cortex of the TrkB hypomorphic mice are similar to those in
individuals with schizophrenia. Representative pseudocoloured autoradiograms show the decreased expression of tyrosine kinase
Trk (tropomyosin-related kinase) receptor B (TrkB), 67 kD isoform of glutamic acid decarboxylase (GAD67) and parvalbumin (PV) mRNAs
in mice that are heterozygous or homozygous for the floxed TrkB (fBZ) locus. In each graph, bars that do not share the same letter
(a, b or c) are significantly different (p<0.05). The mean (SD) expression level of each transcript is reduced in a gene-dose dependent
fashion. F, Fisher’s F distribution resulting from the analyses of variance; the subscript numbers indicate the corresponding degrees of
freedom. nCi/g, nanoCuries/gram; WT, wild type. Modifed, with permission, from REF. 31 © (2005) Society for Neuroscience.
Investigating the pathophysiological process
The findings reviewed above provide evidence for both
a pathological entity (deficient chandelier cell-mediated
inhibition in pyramidal neurons) and a pathogenetic
mechanism (reduced neurotrophin signalling through
the TrkB receptor) in the DLPFC, the dysfunctional
activation of which is associated with a core component
(working memory deficits) of the clinical syndrome
of schizophrenia. However, the explanatory strength of
these findings, and their relevance to the development
of new treatment interventions, requires the demonstration of a pathophysiological process by which this
pathological entity could give rise to this component of
the clinical syndrome.
In this regard, it is of interest that gamma band
oscillations, which reflect the synchronized firing of
neuronal networks at 30–80 Hz, are induced and
sustained in the DLPFC during the delay period of
working memory tasks94. In addition, the amplitude,
or power, of gamma band oscillations in the DLPFC
seems to increase in proportion to working memory
load95. In the frontal cortex of individuals with schizophrenia, phase-locking of gamma activity in response
to the stimulus onset is impaired96, and the power of
gamma band oscillations in the DLPFC is reduced
during the delay period of a working memory task97.
Interestingly, different subpopulations of GABA
neurons seem to be specialized to selectively regulate the
output of pyramidal cells, giving rise to oscillatory activity
in different frequency bands98–100. For example, networks
of parvalbumin-expressing, fast spiking GABA neurons
NATURE REVIEWS | NEUROSCIENCE
in the middle cortical layers, formed by both chemical
and electrical synapses, give rise to oscillatory activity in
the gamma band range, whereas multipolar bursting
GABA neurons in the superficial layers that express both
parvalbumin and calbindin give rise to theta frequency
(4–7 Hz) oscillations100. The coordinated oscillatory
context that is provided by these networks of inhibitory
neurons is thought to create the discrete temporal structure that is necessary for ensembles of pyramidal neurons
to perform specific functions, such as those involved in
working memory.
So, a deficit in the synchronization of pyramidal cells,
which results from impaired perisomatic inhibition by
parvalbumin-expressing GABA neurons, might contribute to the reported deficits in gamma band oscillations,
and, consequently, to working memory dysfunction,
in individuals with schizophrenia. Several features of
parvalbumin-expressing neurons, and of their changes in
schizophrenia, could explain how this might occur. First,
the axonal arborizations of individual chandelier neurons
are highly divergent and target the axon initial segments
of a large number of pyramidal neurons.A single chandelier cell can provide inputs to >200 pyramidal neurons
within a 100–150 µm radius101 and can thereby regulate
the firing of local groups of pyramidal neurons98. Second,
in the monkey DLPFC, parvalbumin-expressing GABA
neurons and pyramidal cells share certain excitatory
inputs, including projections from neighbouring pyramidal neurons and from the mediodorsal thalamus102–104.
Excitatory input from these sources stimulates both
parvalbumin-expressing and pyramidal neurons
VOLUME 6 | APRIL 2005 | 3 2 1
REVIEWS
simultaneously, which results in a secondary, temporally
delayed perisomatic inhibitory input to pyramidal neurons. This disynaptic inhibitory input seems to limit
the window of time, and thereby increases the temporal
precision, for the summation of the excitatory inputs that
are needed to evoke pyramidal neuron firing105. Consequently, a deficiency in inhibitory perisomatic input to
pyramidal neurons would be expected to reduce the
magnitude of pyramidal cell synchrony, and, therefore,
the power of gamma band oscillation, in the DLPFC.
This interpretation predicts that some changes in parvalbumin-expressing GABA neurons in schizophrenia
represent compensatory, but inadequate, responses to the
deficit in GABA synthesis in these neurons. For example,
by buffering presynaptic Ca2+ transients, parvalbumin is
thought to reduce the Ca2+-dependent facilitation of
GABA release106. During periods of repetitive firing, parvalbumin binds Ca2+ molecules, thereby reducing the
level of residual intraterminal Ca2+, which results in
decreased GABA release. Consistent with this interpretation, in parvalbumin-knockout mice, GABA release from
fast-spiking neurons is facilitated and is associated with
an increase in the power of gamma band oscillations106.
Similarly, although the level of GAT1 does not seem to
affect single inhibitory postsynaptic currents (IPSCs), the
blockade of GABA reuptake prolongs the duration of
IPSCs when synapses that are close to each other are
synchronously activated107. The prolongation of IPSCs, in
turn, leads to an increased probability of IPSC summation and, therefore, enhanced efficacy of IPSC trains. This
observation is of particular relevance to the inputs of
chandelier neurons to pyramidal cell axon initial segments, where the GABA synapses are close together and
the presynaptic action potential reaches them almost
simultaneously. So, a combined reduction in parvalbumin and GAT1 proteins in the chandelier axon
cartridges of individuals with schizophrenia could function synergistically to increase the efficacy of GABA
neurotransmission at pyramidal cell axon initial segments during the types of repetitive activity that are
associated with working memory. However, these compensatory mechanisms and the upregulation of postsynaptic GABAA receptors are not adequate to overcome
the effects of decreased GABA synthesis in schizophrenia.
Treatment implications
BENZODIAZEPINE
Benzodiazepines bind to GABAA
receptors, where they increase
the frequency of opening of Cl–
channels in the presence of
GABA, but do not directly open
channels in the absence of
GABA. At present, the available
benzodiazepines are not selective
for GABAA receptors that
contain the α2 subunit, and so
produce a range of effects, such
as the sedation mediated by the
α1 subunit, which can impair
cognitive processes.
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| APRIL 2005 | VOLUME 6
The real value of understanding the pathophysiology of
schizophrenia rests in the prediction of novel targets
for pharmacological intervention. The observations
reviewed above indicate that drugs with selective agonist
activity at α2 subunit-containing GABAA receptors
could provide an effective approach for enhancing
chandelier neuron inhibition of DLPFC pyramidal
neurons in schizophrenia, by increasing the synchronization of pyramidal cell firing at gamma frequencies,
and consequently improving working memory function108. The α2 subunit of the GABAA receptor represents
a selective target for enhancing inhibition at the axon
initial segment of pyramidal neurons because it is predominantly restricted to this location54. In addition, the
increased density of α2 containing GABAA receptors at
pyramidal neuron axon initial segments in individuals
with schizophrenia58 indicates that it might be possible
to devise dosing strategies that would activate these
receptors without affecting synaptic sites in other
brain regions that have normal levels of the GABAA
receptor α2 subunit. Such differential activation could
reduce potential side effects.
Drugs that directly activate α2-containing GABAA
receptors independently of the presence of GABA, or
those that generally increase the firing rate of chandelier
cells, might disrupt the timing of disynaptic inhibition of
pyramidal neurons. Furthermore, agents that inhibit
GABA reuptake non-selectively could function too
broadly, and, in individuals with schizophrenia, the
decrease in the level of GAT1 expression in chandelier
neurons indicates that the brain has already used this
compensatory approach. By contrast, drugs that augment
the release of GABA by chandelier cells during normal
firing, or those that enhance the postsynaptic response to
the release of GABA from chandelier cell axons, such as a
GABAA α2-selective BENZODIAZEPINE, might be expected to
improve disynaptic inhibition. So, treatment with an
α2-selective benzodiazepine would be predicted to augment the postsynaptic inhibitory response at pyramidal
neuron axon initial segments in a manner that incorporates the crucial timing of chandelier neuron firing,
which is essential for synchronizing pyramidal neuron
activity. Furthermore, as the anxiolytic effects of benzodiazepines seem to be mediated by α2 subunit-containing
GABAA receptors109, α2-specific agents might both
improve cognitive function and reduce the stress responses
that have been linked to the exacerbation of psychotic
symptoms in individuals with schizophrenia110.
Understanding schizophrenia
As summarized in FIG. 1, the findings reviewed in this
article converge on the idea that a deficiency in TrkB signalling is a pathogenetic mechanism that produces
reduced GAD67 mRNA expression and GABA synthesis
in the parvalbumin-expressing subpopulation of GABA
neurons in the DLPFC of individuals with schizophrenia.
Despite the apparent compensatory responses, which
include a decrease in the levels of presynaptic GAT1 and
parvalbumin, and upregulation of postsynaptic GABAA
receptors, the resulting pathophysiological process —
changes in the perisomatic inhibitory regulation of pyramidal neurons that are required for gamma frequency
oscillations — contributes to the impairments in working memory function that represent a core feature of the
clinical syndrome of schizophrenia. However, these
abnormalities in GABA neurons are unlikely to be the
only contributors to working memory dysfunction in
this disorder. For example, changes in dopamine and
glutamate neurotransmission in the DLPFC also seem to
be involved111,112. Interestingly, in the monkey DLPFC,
dopamine terminals provide synaptic inputs to parvalbumin-expressing, but not calretinin-expressing, GABA
neurons113, and parvalbumin-positive cortical neurons
express a combination of glutamatergic receptor subunits
that differs from those in other populations of GABA
neurons114.
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REVIEWS
The abnormalities in GABA neurons that contribute
to the working memory disturbances and the resulting
clinical features of schizophrenia might also have a role in
the dysfunction of other cortical regions that have been
associated with reduced gamma band synchrony115.
The extent to which they can account for other clinical
features (for example, psychosis) of the illness remains to
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Acknowledgements
Work by the authors cited in this manuscript was supported by
grants from the National Institutes of Health and by a National
Alliance for Research on Schizophrenia and Depression Young
Investigator Award (T.H.). The authors thank M. Brady and
L. Konopka for excellent assistance with the figures and text.
Competing interests statement
The authors declare competing financial interests: see Web version
for details.
Online links
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
BDNF | GAD65 | GAD67 | GAT1 | TrkB
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