Brain Research Reviews 31 Ž2000.

251–269
www.elsevier.comrlocaterbres

Interactive report

Emerging principles of altered neural circuitry in schizophrenia 1

a,b,)
Francine M. Benes
a
Laboratory for Structural Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA
b
Department of Psychiatry, HarÕard Medical School, Boston, MA 02178, USA
Accepted 7 August 1999

Abstract

This paper presents an overview of recent microscopic studies that have sought to define how limbic circuitry may be altered in
postmortem schizophrenic brain. The discussion is organized around several basic questions regarding the manner in which interconnec-
tions within and between the anterior cingulate cortex and hippocampal formation and involving the glutamate, GABA and dopamine
systems may contribute to the pathophysiology of this disorder. The answers to these questions are used to derive several conclusions
regarding circuitry changes in schizophrenia: 1. Schizophrenia is not a ‘typical’ degenerative disorder, but rather it is one in which
excitotoxicity may contribute to neuronal pathology, whether or not cell death occurs; 2. Three or more neurotransmitter systems may be
simultaneously altered within a single microcircuit; 3. Each transmitter system may show circuitry changes in more than one region, but
such changes may vary on a region-by-region basis; 4. The pathophysiology of schizophrenia may involve ‘mis-wirings’ in intrinsic
circuits Žmicrocircuitry. within a given region, but significant changes are probably also present at the level of interconnections between
two or more regions within a network Žmacrocircuitry.; 5. While some microscopic findings appear to be selectively present in
schizophrenia and be related to a susceptibility gene for this disorder, others may also be present in patients with bipolar disorder; 6.
Although some of the circuitry changes seen in schizophrenia and bipolar disorder seem to be associated with neuroleptic exposure, most
are not and may reflect the influence of non-specific environmental factors such as pre- andror postnatal stress; 7. Normal postnatal
changes at the level of both macro- and microcircuitry within the limbic system may serve as ‘triggers’ for the onset of schizophrenia
during adolescence. Taken together, these emerging principles can provide a framework for future postmortem studies of schizophrenic
brain. q 2000 Elsevier Science B.V. All rights reserved.

Keywords: Anterior cingulate; Hippocampus; Limbic; GABA; Glutamate; Dopamine; Development

Contents
1. Introduction . ....................................................................... 252

2. Limbic lobe findings in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

2.1. Is there evidence of degeneration? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2.2. Which neurotransmitter systems are affected in schizophrenia? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
2.3. Are there regional differences in the types of circuitry changes? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.4. Does schizophrenia involve abnormalities at the level of macrocircuitry? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
2.5. Are the circuitry changes detected specific to schizophrenia? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
2.6. How could normal development ‘trigger’ the onset of schizophrenia?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262

Conclusions . ......................................................................... 263

Acknowledgements . ..................................................................... 264

References .......................................................................... 265

)
Tel.: q1-617-855-2401; Fax: q1-617-855-3199; E-mail:benesf@mclean.harvard.edu
1
Published on the World Wide Web on 12 November 1999.

0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 5 - 0 1 7 3 Ž 9 9 . 0 0 0 4 1 - 7
252 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
1. Introduction
In 1878, Broca designated a rim-like confluence of
cortex along the mid-sagittal surface of mammalian brain
as ‘le grande lobe limbque’ w44x. Comprised primarily of
the cingulate gyrus and hippocampal formation, the limbic
lobe has shown remarkable conservation during the phylo-
genesis of mammalian brain. Based on this observation,
Broca postulated that this structure might be of central
importance to the processing of the emotional components
of cognitive behavior. More recently, Paul MacLean w111x
extended this concept by suggesting that emotional disor-
ders, such as schizophrenia, might involve abnormalities in
the organization and functioning of the extended limbic
system. Consistent with this idea, recent postmortem stud-
ies of the cingulate cortex and hippocampal formation
have suggested that there may be subtle alterations in the
neural circuitry found within both regions.
This current review will attempt to synthesize the quan-
titative microscopic findings that have been reported in the
limbic lobe of schizophrenic brain. The following ques-
tions regarding the histopathology of this disorder will be
considered: Ža. Is schizophrenia a degenerative disorder?
Žb. How are neurotransmitter systems altered within the
intrinsic circuitry found in the cingulate gyrus and hip-
pocampus? Žc. Are the histopathologic changes observed
in each of these regions similar or different? Žd. Are any of
the changes noted specifically related to a gene for
schizophrenia or could they potentially be found in other
major psychoses and reflect non-specific factors such as
stress or neuroleptic exposure? Že. Can late developmental
changes in the limbic lobe contribute to the start of the
schizophrenic illness during late adolescence and early
adulthood? As the reader will see, the microscopic findings
that have recently been reported to date in the cingulate
gyrus and hippocampal formation can be used to propose
several emerging principles regarding alterations of neural
circuitry within the limbic lobe of schizophrenic brain.
2. Limbic lobe findings in schizophrenia
2.1. Is there eÕidence of degeneration?
The idea that a neurodegenerative process may con-
tribute to the schizophrenic syndrome was first posed by
Kraeplin w102x in the late nineteenth century, but has
remained unanswered until very recently. Early histopatho-
logical studies of this disorder have revealed a variety of
methodologic flaws and technological inadequacies that
stood in the way of a conceptual breakthrough in this field
during most of the 20th Century w7x. Over the past 20
years, however, major advances in our understanding of
how to quantitate central nervous system structure have
made it possible to address this question in a much more
meaningful way. Morphometric studies from several dif-
ferent laboratories have suggested that there may be a
reduction in the volume of the parahippocampal gyrus w45x,
entorhinal region w65x, prefrontal cortex w148x, hippocam-
pus, amygdala and globus pallidus interna w40x in
schizophrenia. In the hippocampus, not all studies have
shown atrophy w82x or neuronal loss w81x, but it seems
likely that this finding may occur to a variable degree in
different patient populations. It is important to emphasize
that when volume loss is present, many different pro-
cesses, some reversible and others irreversible in nature,
could be responsible w7x. On the other hand, when volume
loss is not present, this does not preclude the possibility
that important histopathologic changes may be present at
the microscopic level.
In order to rule-in Žor rule-out. the presence of neuronal
cell death, detailed cell counting approaches are generally
required. Consistent with the volume loss observed in
some patients with schizophrenia, a reduction in neuronal
numbers has been detected in the anterior cingulate cortex
w17,22x and hippocampus w20,54,90x of schizophrenics.
Other regions also show evidence of neuronal loss and
have been reviewed elsewhere w12x. There is mounting
evidence that a loss of nonpyramidal neurons may occur in
both schizophrenia and affective disorder w20,22,27,172x.
Not all cell counting studies of schizophrenia, however,
have revealed a decrease in the density of neurons
w4,24,81,124,148x. A variety of factors, including patient
samples, tissue processing, regions studied and cell count-
ing methodology could all help to explain the variability of
these findings from one study to another w12x. It seems
likely, however, that neuronal loss is neither necessary nor
sufficient to explain the occurrence of schizophrenia. When
present, however, it seems likely that it would play a
contributory role in the pathophysiology of this disorder.
A reduction in the density or total numbers of neurons
in a brain region is not sufficient to prove that a degenera-
tive process has occurred. It is generally accepted in the
field of neuropathology that ‘typical’ neuronal degenera-
tion, like that seen in Huntington’s chorea or Alzheimer’s
disease, is accompanied by a ‘gliotic reaction.’ The latter
consists of an increase in the number of non-neuronal
elements Ži.e., glial cells. that are involved in the removal
of cellular debris accrued from dying neurons. It is note-
worthy that several cell counting studies have systemati-
cally evaluated whether the density of glial cells is in-
creased in various regions of schizophrenic brain and have
found no evidence for a gliotic reaction w17,22,65,138,148x.
The absence of gliosis in schizophrenia provides a com-
pelling argument that necrotic cell death w41,66,129x does
not play a role in the pathophysiology of this disorder. The
latter conclusion does not, however, exclude the possibility
that an apoptotic w66,84x form of neuronal loss may be
occurring.
Are there any clues that could shed some light on
whether apoptosis may play a role in the pathophysiology
of schizophrenia? Closer scrutiny of the findings reported
 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
in cell counting studies of schizophrenic brain reveals a
potentially interesting pattern. In both the anterior cingu-
late and prefrontal cortex w22x, as well as the hippocampal
formation w20x, a preferential decrease in the density of
nonpyramidal cells has been reported. This latter neuronal
subtype is considered to be a population of local circuit
cells that are largely GABAergic in nature w63,64x. Al-
though this change shows a very discrete localization in
only some regions, a decrease of inhibitory modulation in
a key circuit could nevertheless have a significant impact
on information processing Žsee Section 2.4.3...
How could interneurons be adversely affected in both
SZ and manic depression? Apoptosis is a cellular mecha-
nism associated with neuronal death primarily during nor-
mal ontogeny w37,47,66x, but oxidative stress is one of its
variants that can occur with excessive glutamatergic activ-
ity w51x. Glucocorticoid hormones, together with increased
glutamatergic activity, can result in excitotoxic cell death
w143x. It is well-established that all forms of stress result in
an increased release of glucocorticoids, steroid hormones
that bind to receptors abundantly present throughout the
hippocampus and cortex w143x. Of particular relevance to
the current discussion is the fact that w 3 Hxcorticosterone
shows the most extensive nuclear binding in sector CA2
w117,157x where nonpyramidal cells seem to be selectively
decreased in schizophrenia w20x. Accordingly, increased
levels of glucocorticoid hormone associated with the stress
response could potentially exert a potent toxic effect on
neurons in this sector, particularly if they were simultane-
ously receiving heightened glutamatergic activity. It is
relevant to ask then, whether a high degree of sensitivity to
circulating glucocorticoid hormone could potentially pre-
dispose sector CA2 to a selective decrease of nonpyrami-
dal cells in schizophrenic and manic depressive subjects
exposed to stress Žsee Section 2.2.2... If so, a disturbance
of the hippocampal glutamate system acting synergistically
to promote oxidative stress would be required for such a
change to occur.
2.2. Which neurotransmitter systems are affected in
schizophrenia?
There are many different transmitters that can poten-
tially be implicated in the pathophysiology of schizophre-
nia. Indeed, recent neurochemical studies have pointed to
possible changes in the glutamate, GABA, dopamine, sero-
tonin and acetylcholine systems in this disorder Žfor a
review, see Ref. w149x.. Little is known, however, as to
whether two or more of these transmitter systems within a
single microcircuit may be simultaneously abnormal and,
if so, how such changes might result in anomalous interac-
tions pre- andror post-synaptically within such a circuit.
In a series of recent postmortem studies, the design in-
cluded systematic model generation and testing in order to
address this issue at the microscopic level w15x. In micro-
scopic studies of postmortem schizophrenic brain, the three
253
transmitter systems that have thus far been studied in detail
include glutamate, GABA and dopamine. Toward this end,
a combination of cell counting, receptor binding auto-
radiography and immunocytochemistry have been em-
ployed. In the discussion below, the findings concerning
each transmitter system obtained using quantitative cyto-
chemical strategies, together with circuitry modelling are
summarized. Wherever possible, the microscopic results
presented will be related to neurochemical studies reported
by other groups.
2.2.1. The glutamate system
Early attempts at modelling for postmortem results had
suggested that there may be alterations in the arrangements
of neuronal clusters in layer II of the anterior cingulate
cortex w16x. To test the hypothesis that there might be an
increase of vertical axons passing between adjacent clus-
ters in this lamina, an immunocytochemical localization of
the phosphorylated epitopes of the 200K neurofilament
protein ŽNFP200K. was used to visualize such fibers in
human postmortem cortex. The results demonstrated a
25% higher density of vertical axons in anterior cingulate
cortex of schizophrenic subjects when compared to normal
controls w21x; horizontal axons did not show this change. In
a subsequent replication study, this same pattern was again
found in cingulate cortex, but not the prefrontal area of
schizophrenics w9x. In yet another replication study, this
finding was again observed using an entirely different
method in which antibodies against glutamate were em-
ployed. In this case, the effect size was much larger and a
robust increase Ž78%. in the density of glutamate-IR verti-
cal axons in layer II and upper portions of layer IIIa was
found w25x. This latter finding provided further support for
the idea that these vertical fibers might be incoming
excitatory afferents from other cortical or perhaps even
subcortical regions.
As shown in Fig. 1, this latter increase in the number of
glutamatergic inputs to layer II of the anterior cingulate
cortex could potentially play a role in the induction of
excitotoxicity, particularly if the flow of activity along
these axons were also increased Žsee below.. Consistent
with this idea, a recent PET scanning study has reported an
increase of metabolic activity in relation to auditory hallu-
cinations that occurred in the cingulate gyrus of
schizophrenic subjects w151x. If there is an increase of
glutamatergic tone in the cingulate gyrus in this disorder,
then a secondary increase would also be expected to occur
in the hippocampal formation because this region receives
a substantial descending flow of afferent activity via the
cingulum bundle ŽFig. 2.. Is there any evidence for an
actual increase of excitatory activity in the hippocampal
formation of schizophrenics? As with the cingulate cortex,
another recent PET scanning study has also demonstrated
an elevation in the baseline metabolism of this latter region
w83x. Accordingly, both components of the limbic lobe
show increased activity in schizophrenia.
254 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269

Fig. 1. A working model for a ‘mis-wiring’ of dopaminergic fibers in layer II of anterior cingulate cortex from schizophrenic brain. Normal control circuit:
A pyramidal neuron receives inhibitory inputs from two GABAergic interneurons, and there are two glutamatergic afferent fibers travelling vertically
toward layer I where they form excitatory synapses with distal portions of the pyramidal cell apical dendrite. Each GABAergic cell has one dopaminergic
varicosity in contact with its cell body, while the pyramidal neuron has two. Schizophrenic circuit: A pyramidal neuron receives inhibitory input from only
one GABAergic interneuron, but there are four glutamatergic afferent fibers travelling vertically toward layer I and forming excitatory synapses with the
pyramidal cell dendrite. The GABAergic interneuron has two dopaminergic varicosities forming contacts with its cell body, while the pyramidal neuron
receives only one such input. This model suggests that the schizophrenic circuit may have superabundant glutamatergic excitatory inputs w25x, and together
with an intrinsic defect in GABAergic inhibitory modulation w31x would result in excessive excitatory outflow of activity from the pyramidal neuron to its
projection sites in other brain regions. If the dopaminergic inputs are inhibitory in nature, an increase of these afferents to GABAergic neurons would tend
to reduce further the amount of inhibitory modulation that could be exerted on the pyramidal neuron, particularly under conditions of stress when the
release of dopamine may be increased Žsee text for details.. Such a circuit could help to explain the loss of habituation and over-inclusiveness that occurs in
schizophrenia w59x. Adapted from Ref. w26x.

Do postmortem studies of the hippocampus also provide
corroborative data in support of this latter concept? Neuro-
chemical investigations have suggested that nonNMDA-
sensitive glutamate receptors might be decreased in the
hippocampal formation of schizophrenics w80,95,96x. Fur-
ther support for this idea has come from a recent histo-
chemical study of the GluR 5,6,7 subunit of the kainate
receptor w86x. A preferential localization of this protein to
the apical dendritic shafts of pyramidal cells, particularly
in sectors CA3 and CA2 was reported w77x. Subsequently a
blind, quantitative analysis revealed that there was a de-
crease of GluR 5,6,7-IR dendrites in sectors CA3 and CA2
in schizophrenics when compared to a group of age and
PMI-matched normal controls. This difference in the
schizophrenic group was seen in the stratum radiatum and
stratum moleculare, but not the stratum oriens w101x. Distal
portions of sector CA1, i.e., those areas closer to the
prosubiculum, did not show any difference in the
schizophrenics. A matched group of manic depressives did
not show a significant change in any of the sectors or
laminae examined, whether or not they were treated with
neuroleptic drugs. Taken together, these findings are con-
sistent with the idea that the expression of the kainate-sen-
sitive glutamate receptor may be reduced in schizophrenia.
Is such a decrease a sign of a primary dysregulation of this
receptor protein or possibly to a compensatory down-regu-
lation? The fact that there was little change in the stratum
oriens where the basal dendritic branches of pyramidal
neurons are found suggests that this change is not dis-
tributed uniformly throughout the intracellular space of
projections cells ŽFig. 4.. Since the stratum radiatum and
stratum moleculare, where the GluR 5,6,7 subunit expres-
sion is decreased, are known to contain both intrinsic and
extrinsic glutamatergic inputs, respectively, to sectors CA3,
2 and 1 w139x, an increased flow of excitatory activity
through these two laminae could be occurring in
schizophrenic hippocampus and causing a compensatory
down-regulation Žsee Section 2.4...
2.2.2. The GABA system
The observation that nonpyramidal neurons were de-
creased in density in both the anterior cingulate cortex w22x
and hippocampal formation w20x has suggested the possibil-
ity that these cells might be associated with a decrease of
GABAergic function in these regions w53x. Neurochemical
evidence in support of this idea has come from studies
showing an increase of w 3 Hxmuscimol binding w79x, a
decrease of glutamate decarboxylase w38x and a reduction
in GABA uptake in the cortex w152x and hippocampus
w137x of schizophrenic brain. More recently, an ICC local-
ization of the calcium binding protein parvalbumin has
demonstrated a reduction of cells showing this immuno-
reactivity in the cingulate cortex of schizophrenics w5x.
Since this peptide immunoreactivity appears to be prefer-
entially associated with interneurons believed to be in-
hibitory basket cells w50x, these latter results support the
 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269 255

Fig. 2. A schematic diagram depicting a macrocircuit consisting of the anterior cingulate cortex and hippocampus in a normal control versus a
schizophrenic. The circuitry illustrated in layer II of the normal control and schizophrenic is similar to that shown in Fig. 1, except that the dopamine
projections are not included. The increased vertical axons passing through the superficial layers of the cingulate region may be cortico-cortical afferents or
inputs from the anterior thalamic nucleus, the basolateral nucleus of the amygdala or the subiculum. The changes observed in schizophrenics are consistent
with a model in which there is an increased downflow of excitatory activity to deeper laminae of the cingulate region, as well as other regions, such as the
hippocampus, with which it is connected. If the hippocampus is receiving excessive amounts of excitatory activity from other regions, such as the cingulate
cortex, and possibly also the prefrontal area w176x, it could induce an overall increase in its level of activation. Adapted from Ref. w11x.

hypothesis that GABA cell loss or dysfunction could be a
feature of schizophrenia ŽFig. 1.. The alternative possibil-
ity that the amount of parvalbumin present within a normal
number of cells may have simply fallen below the level of
detection cannot as yet be excluded. Other studies de-
scribed elsewhere in this volume have used a similar
approach to study neurons with immunoreactivity for cal-
bindin and calretinin in the dorsolateral prefrontal cortex
w57x. There are many different subtypes of nonpyramidal
neuron that use GABA as a neurotransmitter and each of
these could theoretically show a unique pattern of change
in schizophrenic cortex Žsee Fig. 3..
If the nonpyramidal cells that are reduced in density in
the cingulate cortex w22x and hippocampus w20x were
GABAergic in nature, a compensatory up-regulation of the
GABA A receptor on postsynaptic pyramidal neurons would
be expected to occur w23x. Using a high resolution autora-
diographic technique to localize receptor binding on indi-
vidual neuronal cell bodies, bicuculline-sensitive w 3 Hx
muscimol binding was found to be increased by 84% in
256 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269

Fig. 3. A schematic diagram depicting GABA A receptor binding activity in the hippocampal formation of normal Žpyramidal neurons A and C. and
schizophrenic Žpyramidal neurons B and D. subjects. Sector CA1: Pyramidal neuron A representing normal controls shows three GABA A receptors in
relation to each GABAergic input. Pyramidal neuron B, representing the schizophrenic circuit, also shows three GABA A receptors near the intact GABA
input, but six receptors on the opposite side of the cell where the inhibitory GABA A input is missing. The disinhibitory GABA neuron is present in both
the normal and schizophrenic circuit and the inhibitory GABA cells in both cases show three GABA A receptors. Sector CA3: Pyramidal neuron C in the
normal control circuit shows a similar set of inhibitory and disinhibitory inputs and GABA A receptors as shown for sector CA1. Pyramidal neuron D,
however, representing the schizophrenic circuit, shows a normal amount of GABA A receptors Žthree. in relation to the two intact inhibitory GABA inputs;
but, a loss or decrease of disinhibitory GABAergic activity results in a compensatory upregulation of GABA A receptors Žsix. on the two inhibitory GABA
cell bodies. Adapted from Ref. w19x.

layer II and 74% in layer III of the cingulate cortex w29x. A
similar pattern was observed in the dorsolateral prefrontal
cortex where the increase was principally noted on pyrami-
dal neurons w30x. In the hippocampal formation w19x, an
increase of this receptor has also been found, but in this
case, the increase occured preferentially in sectors CA4,3
and 2, but not CA1 ŽFig. 4. in schizophrenia. In sectors
CA3 and CA2, the most striking increase of the GABA A
receptor binding activity was in the stratum oriens, where
potent inhibitory modulation of pyramidal cells is exerted.
Are there any clues as to the kind of mechanismŽs. that
could play a role in the generation of a GABA defect in
schizophrenia? As discussed above in relation to cell
counting, an intriguing possibility are the glucocorticoid
hormones that have the ability to bind directly to the
GABA A receptor w158x and increase its activity w103,
104,112x. Is it possible that the up-regulation of this recep-
tor noted in sectors CA3 and CA2 of SZs w19,33x could
conceivably be related, perhaps in part, to increased gluco-
corticoid release. This is a potentially important possibility
to consider because these hormones are released into the
bloodstream in abundant amounts in association with the
acute stress response, although they are thought to increase
GABAergic inhibitory activity, rather than decrease it
w68,120,130,178x. In any case, it is theoretically possible
that the increase of GABA A receptor binding noted in the
cortex and hippocampus of schizophrenics may not be a
compensatory change in response to decreased GABAergic
activity. Rather, this change could be the sequela of un-
remitting stress in individuals with chronic psychosis. This
idea is given further credibility by the observation that
glucocorticoids can cause an increase of GABA A binding,
 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269 257

Fig. 4. A model for alterations of the trisynaptic pathway in the hippocampal formation of schizophrenic brain. Normal Control Circuit: There are
pyramidal neurons indicated in sectors CA3, CA2 and CA1. The pyramidal neuron in CA3 sends a Schaffer collateral branch that sweeps upward and
terminates in the stratum radiatum ŽSR. of CA1. Each pyramidal cell receives inhibitory inputs from a GABAergic interneuron projecting both to its soma
in the stratum pyramidal ŽSP. and to the stratum oriens ŽSO.. The GABA neuron in CA2 is also depicted as sending a collateral branch that forms a
GABA-to-GABA contact with an inhibitory interneuron in CA3. Neuroleptic-free Schizophrenic Circuit: The GABAergic neuron in CA2 is missing and
there is an associated loss of inhibitory terminals within the SP and SO of both CA2 and CA3. CA1 is unaffected. Neuroleptic-treated Schizophrenic
Circuit: The GABAergic neuron in CA3 has sprouted additional axonal branches that project to the SO of both CA3 and CA2. This GABAergic neuron is
also receiving a sprouted GABA terminal, but its site of origin is not indicated.

without any change in the benzodiazepine site Žfor a
review, see Ref. w134x.. It is noteworthy that a similar
uncoupling in the regulation of this receptor complex has
been observed recently in the hippocampus of schizophren-
ics w33x. Our cortex study showed a decrease of the
beuzodiazepine receptor in schizophrenics w154x. Since
glucocorticoids potentiate excitotoxicity w143x and
GABAergic cells in the hippocampus w131,183x show a
marked susceptibility to such injury mediated through
kainate receptors Žsee Section 2.2.1.., the stress response
offers a plausible way of explaining not only the reduced
density of nonpyramidal neurons, but also the uncoupled
increase of GABA A receptor binding activity in
schizophrenia. The fact that kainate-sensitive glutamate
receptors are especially abundant in sectors CA3 and CA2
w121x and appear to be reduced in the hippocampus of
schizophrenics w95,96,80,101x gives further credence to
this idea.
Another strategy that has been used to study GABAer-
gic cells in the limbic lobe of schizophrenic brain is
immunocytochemistry. The 65 kDalton isoform of gluta-
mate decarboxylase ŽGAD65 . is prefentially localized to
neuronal cell bodies and provides a potentially sensitive
and reliable means of studying the distribution of
GABAergic interneurons w93x. Using a technique that was
adapted to human postmortem tissues, no overall differ-
ence in the density of GAD65 -immunoreactive terminals
was observed, however, in the hippocampus of
schizophrenic subjects w164x. There was, however, a strik-
ing positive correlation between the dose of neuroleptic
medication and the density of GABA terminals in sectors
CA3 and CA2, particularly in the stratum oriens where the
GABA A receptor showed the most marked increase w19x.
As suggested in the model shown in Fig. 4, antipsychotic
medication could theoretically be capable of inducing a
trophic sprouting of GABAergic terminals in the hip-
258 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
pocampal subfields Žsee Section 2.4.2... The fact that the
stratum oriens also showed the largest increase of GABA A
binding activity in schizophrenics w19x is consistent with
the hypothesis that there is a compensatory up-regulation
of this receptor in schizophrenia. This lamina may, there-
fore, be a preferential site not only for GABAergic dys-
function in schizophrenia, but also the therapeutic
influence of neuroleptic drugs. Networks of GABAergic
interneurons within the stratum oriens have recently been
shown to play a central role in the generation of theta
rhythms and in the coupling of these oscillations with
pyramidal cell activity w55x. Thus, an appreciable defect of
GABAergic function in the stratum oriens could poten-
tially contribute significantly a disturbance of electrical
activity generated in the hippocampal formation in
schizophrenia Žsee Section 2.4...
2.2.3. Dopamine
The third neurotransmitter for which there now is mi-
croscopic evidence suggesting an abnormality in
schizophrenia is dopamine. Although many studies have
demonstrated that patients with schizophrenia show a
marked up-regulation of the dopamine D2 receptor in the
corpus striatum and other cortical areas w52,91,100,
110,123,146x, it is now well-established that neuroleptic
drugs are largely responsible for a rapid and marked
increase of this receptor binding activity w91,100,107,
165,175x. Other markers for this system, including the
levels of dopamine itself w38,54,110,165x and various other
parameters related to its synthesis, degradation
w145,180,181x and re-uptake w146x have not yielded any
consistent pattern of change in schizophrenic brain. These
latter neurochemical studies, though employing very sensi-
tive techniques, lack the spatial resolution needed to detect
subtle changes at the synaptic level. To understand how
the dopamine system is integrated within corticolimbic
circuitry in schizophrenia, it is necessary to use micro-
scopic techniques to evaluate its fiber projections. Al-
though it is not possible to directly visualize dopamine in
human postmortem tissues, tyrosine hydroxylase ŽTH., the
rate-limiting enzyme in the synthetic pathway for catechol-
amines, can now be reliably localized. While TH is not
specific to the dopamine system, it has been found to
selectively visualize dopamine fibers in both monkey and
human cortex w2,73,107,122,142,179x. Computer-assisted
microscopic analyses of TH-immunoreactivity have been
applied to both the anterior cingulate w26x and entorhinal
w2x cortices and have revealed a decrease of fibers and
varicosities in the schizophrenics. In the cingulate cortex,
this change was much less pronounced and was noted only
in layers V and VI; however, this reduction in the density
of varicosities was associated with neuroleptic exposure, as
¨ and drug-free subjects did not show this differ-
drug-naıve
ence.
Dopamine fibers have been found to interact with both
pyramidal w75,76x and nonpyramidal w31,168x neurons. Al-
though most contacts of dopamine fibers appear to be
non-synaptic in nature w6x, each bouton appears to make at
least one synaptic contact w147x and most are axodendritic
in nature w75,168x. Those appositions that are found on cell
somata, though not synaptic w168x, may nevertheless be
functional in nature, because both D1 and D2 receptor
binding activity w170,171x, as well as the associated mes-
senger RNAs w85x have been localized on both pyramidal
and nonpyramidal cell bodies. Neuropharmacologic studies
have suggested that dopamine, which acts as a modulator
of other neurotransmitters in the cortex w46x, can specifi-
cally influence the activity of cortical GABA neurons
w74,135,136x.
Based on these observations from animal investigations,
it was appropriate to consider whether schizophrenia might
involve an alteration in the interaction of dopamine fibers
with different populations of cortical neurons. This idea
seemed particularly relevant since a PET study had demon-
strated that manipulation of this transmitter system can be
used to modulate the impaired cognitive-task-induced acti-
vation of the anterior cingulate cortex seen in schizophrenic
patients w60x. To characterize the dopamine system in
postmortem SZ brain, the density of tyrosine hydroxylase-
immunoreactive ŽTH-IR. varicosities in apposition with
pyramidal neurons versus nonpyramidal neurons was as-
sessed in the anterior cingulate and prefrontal cortices. The
results demonstrated that the density of TH-IR varicosities
in apposition with nonpyramidal cells was three times
higher than that for pyramidal cells w26x. This finding was
only observed in layer II of the cingulate cortex, but not in
any of the other laminae of this region. As depicted in the
model shown in Fig. 1, these latter findings suggested that
there could be a ‘mis-wiring’ of dopaminergic afferents
with respect to intrinsic neurons in the cingulate cortex.
Although several models were considered, only one in
which there was a trophic shift of dopamine fibers away
from pyramidal neurons to interneurons could best explain
the results w15x. Since dopamine appears to be inhibitory to
GABA cells w136x, a relative increase of inhibitory
dopamine inputs to interneurons in layer II could poten-
tially exacerbate the effect of an intrinsic GABAergic
impairment, particularly if these inputs to pyramidal neu-
rons were simultaneously reduced. Such a mechanism
could be operative, even in the absence of any overt
change in the levels of dopamine. Thus, a hyperinnervation
of GABA cells by the dopamine system in the cingulate
cortex could potentially help to explain why blockade of
D 1 and D 2 receptors is effective in relieving the symptoms
of schizophrenia Žsee Fig. 1..
Rodent studies of the dopamine system have demon-
strated a marked increase in the release of this transmitter
in the cortex under conditions of stress w140,163x. Taken
together with the postmortem findings suggesting an in-
crease of dopamine inputs to interneurons occurs in layer
II of cingulate cortex in schizophrenics, it seems plausible
that a stress-related release of inhibitory dopamine could
 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
precipitate a decompensation of a cortical circuit in which
there is an impaired population of GABA cells ŽFig. 1.. In
this setting, an increased outflow of excitatory activity
from pyramidal cells in layers II and V to other regions
with which the cingulate cortex is connected would be
predicted Žsee Fig. 2.. By blocking dopamine receptors,
this decompensated circuit could be returned to a state of
relative compensation. If this model were correct, it would
help to explain the clinical observation that stress can
cause an acute exacerbation of psychosis in schizophrenic
patients, while the administration of neuroleptic drugs can
often induce a prompt remission.
2.3. Are there regional differences in the types of circuitry
changes?
It is often assumed that if a transmitter system is altered
in one region of a diseased brain, another region of the
same brain will show a similar change. Although this
concept could be correct if the two hypothetical regions in
question had a similar organization and connectivity, it
might not be true if the two regions were intrinsically
different in both of these respects. In evaluating the pattern
of change for various markers that have been studied in
postmortem schizophrenic brain, an intriguing pattern can
be discerned. There are three examples of region-to-region
variation of circuitry changes in these studies of post-
mortem schizophrenic brain. The first instance that can be
cited is that for the dopamine system that was discussed in
the section immediately preceding ‘mis-wiring’ of
dopamine fibers was observed in the cingulate cortex, but
not prefrontal cortex w26x. A second example of regional
differences was discussed above in the section on the
Glutamate System. Studies of vertical axons in the anterior
cingulate cortex w9,21,25x revealed a marked increase in
density in layer II and upper portions of IIIa. However,
there were no differences noted in the dorsolateral pre-
frontal cortex of schizophrenics in two separate studies
w9,25x. Like the anterior cingulate cortex, the entorhinal
region, also showed a significant increase in the density of
glutamate-IR vertical axons w109x. Why would the anterior
cingulate and entorhinal cortices show an increase of
vertical axons, while the dorsolateral prefrontal area does
not? One way of conceptualizing how such a regional
difference in the pattern of findings might occur is to
postulate that these fibers may represent a specific afferent
input, one that shows differences in its distribution among
the three regions studied Žsee Section 2.4..
A third circumstance in which differences in the pattern
of findings have been observed in schizophrenia involves
the GABAergic system. In the anterior cingulate w29x and
prefrontal w30x cortices of schizophrenics, the data obtained
high resolution studies of GABA A receptor binding activ-
ity suggested a model in which there is a decrease of
inhibitory inputs to pyramidal neurons in layer II of these
regions ŽFig. 1.. In sector CA1 of the hippocampal forma-
259
tion w19x, a modest increase Ž10–20%. of this receptor was
also detected on pyramidal neurons ŽFig. 3.. In sector
CA3, on the other hand, the increase of the GABA A
receptor binding activity was much more marked Ž100%.,
but was found primarily on nonpyramidal neurons, rather
than pyramidal cells w18,19x. This latter finding suggested
that GABAergic dysfunction within the stratum pyrami-
dale of CA3 might be associated with disinhibitory in-
terneurons, i.e., GABA cells projecting to other GABA
cells Žfor a discussion, see Ref. w153x., rather than in-
hibitory ones ŽFig. 3.. Most of these GABA-to-GABA
connections probably originate within the hippocampal
formation itself and involve long collateral branches that
travel from one subfield to another w150x. Some of these
disinhibitory fibers may, however, originate in extra-HIPP
sites, such as the septal nuclei, which have been found to
send GABAergic inputs to inhibitory interneurons of sec-
tor CA3 w71x. Not surprisingly, both extrinsic and intrinsic
disinhibitory GABAergic connections in the hippocampus
are thought to play a role in the generation of rapid gamma
oscillations w166,176x, as well as slow theta rhythms
w48,182x. Similar disinhibitory interactions are present
within the stratum oriens where they may also contribute
to the generation of oscillatory rhythms w55x. It is notewor-
thy that the stratum oriens of sector CA3 did show the
most marked up-regulation of the GABA A receptor in
schizophrenia w19x; but, it is impossible to say whether this
change was associated with the processes of pyramidal
cells or GABAergic interneurons intrinsic to this lamina.
Nevertheless, it seems likely that disturbances of GABAer-
gic activity in the stratum oriens of CA3 could be associ-
ated with complex effects on the conduction of electrical
impulses along the trisynaptic pathway.
Overall, the discussion in this section provides evidence
that alterations of the glutamate, GABA and dopamine
systems in the corticolimbic system of schizophrenic brain
may all show variations on a region-by-region basis. The
fact that there are both similarities and differences in
findings across key regions such as the anterior cingulate
cortex, prefrontal region and hippocampal formation, sug-
gests that extrapolation of findings across widely dispersed
brain areas should be avoided.
2.4. Does schizophrenia inÕolÕe abnormalities at the leÕel
of macrocircuitry?
A macrocircuit can be defined as the connectivity that
exists between two or more regions comprising a network
w13x. In considering whether there are alterations at this
level in schizophrenic brain, it is useful to evaluate struc-
tural parameters that may be inferred to represent extrinsic
fibers originating in one region and projecting to another
w13x. Because the issues for various regions are somewhat
different, the discussion in this section is considered sepa-
rately for the anterior cingulate cortex and the hippocam-
pal formation.
260 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
2.4.1. Inferences from studies of anterior cingulate cortex
In animal investigations, macrocircuitry is characterized
by using anterograde andror retrograde tracing techniques.
In studies of postmortem human brain, however, these
approaches are not feasible. An alternative strategy for
learning about macrocircuitry in postmortem studies of
schizophrenia is to employ cytochemical techniques that
allow specific axonal populations to be visualized. As
discussed above in Section 2.2.1., an earlier study in which
NFP200k-IR axons were localized had suggested that exci-
tatory afferents coursing toward the superficial layers of
the anterior cingulate cortex may be increased in
schizophrenics w21x. Although NFP200k is present in virtu-
ally all axons of the brain, this latter conclusion was
possible because it is well-established that afferents from
other cortical regions Žfor a review, see Ref. w61x., the
amygdala w173x and the thalamus w174x all travel to the
superficial layers of this region. In addition, dopaminergic,
sertoninergic, noradrenergic and cholinergic fibers from
the ventral tegmental area w34,162,108x, raphe nuclei
w58,108x, locus coeruleus w106,108x and nucleus basalis of
Meynert w119x, respectively, project as well to the upper
layers of the cingulate cortex; all of these fiber types
probably contain the NFP200k subunit. Is there any way of
further defining the nature of these vertical axons that are
increased in cingulate cortex of SZ brain? Immunocyto-
chemistry provides a potentially useful approach to this
question. As discussed in Section 2.2.1., the use of a
monoclonal antibody against glutamate has made it possi-
ble to visualize this amino acid in human postmortem
cortex and this technique has revealed a dense array of
vertical fibers in the superficial layers of ACCx, but not
PFCx of schizophrenics w25x. Taking together the results of
the two immunolocalizations, it seemed likely that the
fibers showing increases in schizophrenics might be gluta-
matergic in nature, making it unlikely that the monoamin-
ergic systems were their source. Without the help of
tract-tracing technology, however, it is not possible to
specifically define the site of origin of these fibers in a
human postmortem brain.
Are there indirect ways of making inferences regarding
the site of origin that can help to narrow-down the range of
possible loci from which the vertical fibers may have
originated? As noted in the discussion above, the fibers
visualized with both the NFP200K and glutamate ap-
proaches were found to be increased in the anterior cingu-
late w21,25x, but not the dorsolateral prefrontal region
w9,21,25x. A reasonable question to ask is whether the
superficial layers of the cingulate region might receive a
projection that is not present in the dorsolateral prefrontal
area. The basolateral complex of the amygdala presents an
intriguing possibility because layer II of the anterior cingu-
late cortex receives a ‘massive’ projection from this nu-
cleus, while the prefrontal area receives only a sparse
innervation w3,167x. Since the basolateral complex also
sends a substantial projection to the entorhinal cortex, it
seemed relevant to ask whether this latter region might
also show an increase of glutamate-IR vertical axons in
superficial laminae of schizophrenics. A subsequent study
demonstrated a 38% increase of glutamate-IR vertical ax-
ons in the schizophrenic group w109x. Taking together these
various findings, it seems plausible that there may be an
increase of amygdala projections to superficial layers of
ACCx and ERCx in SZ brain. In support of this, there are
cell bodies in the basolateral nucleus of the amygdala that
show intense glutamate-IR similar to that seen in the
vertical axons described above; these latter somata are
believed to be cortical projection neurons w116x. Thus, the
studies of vertical axons in ACCx and ERCx have sug-
gested the possibility that there may be an increased
number of glutamatergic afferents projecting to these re-
gions from the basolateral nuclear complex ŽFig. 2..
2.4.2. Inferences from studies of the hippocampal forma-
tion
For the hippocampus, similar issues can be raised.
Although it is not possible to visualize an actual change in
the conduction of impulses along axons in postmortem
brain, a decrease of the GluR 5,6,7 subunits Žsee Section
2.2.1.. could represent a functional down-regulation sec-
ondary to increased glutamtergic activity w101x. This change
was observed in the stratum radiatum and stratum molecu-
lare, but not the stratum oriens. This latter pattern could
occur if there were an increased flow of glutamatergic
activity along both intrinsic and extrinsic fibers, respec-
tively, that course through these two laminae. In the
stratum moleculare, these fibers would include afferents
from the entorhinal cortex and the basolateral nucleus of
the amygdala. In the stratum radiatum, on the other hand,
they would include projections, such as mossy fibers and
Schaffer collaterals that are intrinsic to the hippocampal
formation Žfor an authoritative review, see Ref. w139x..
Is it possible that an increased flow of excitatory activ-
ity from the basolateral nucleus of the amygdala could
cause changes in the hippocampal GABA system? A pre-
liminary study using picrotoxin infusion into the basolat-
eral complex of awake, freely moving rats w35x, has
demonstrated a marked decrease in the density of GAD67 -
IR terminals on pyramidal neurons in sectors CA3 and
CA2, but not CA1 of drug-treated rats w36x. These results
are consistent with the hypothesis that excitatory activity
originating in the amygdala could stimulate GABAergic
terminals to release GABA Žand also GAD. in sectors CA3
and CA2 Žsee Section 2.2.2.. where fibers from the baso-
lateral complex terminate w139x. Since hippocampal GABA
cells are particularly sensitive to excitotoxic injury medi-
ated through kainate receptors w144,183x, it will be relevant
to determine whether stimulation of the BLn, if sustained,
can eventually lead to an excitotoxic injury in GABAergic
neurons of CA2 where a loss of nonpyramidal cells was
observed in schizophrenics w20x.
 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
2.4.3. Functional implications for proposed macrocircuitry
changes in schizophrenia
Schizophrenics typically show a diminished ability to
habituate and an over-inclusiveness to their perceptions
w59x. Clinical investigations of schizophrenia have demon-
strated abnormalities in electrophysiological parameters,
such as the so-called P50 w1,70x and P300 w114,115x com-
ponents of auditory-evoked responses ŽERPs.. Patients with
this disorder also show impaired pre-pulse inhibition ŽPPI.
to a startle response w42,43x. In these latter three paradigms,
an initial stimulus effectively reduces the response magni-
tude in normal controls; in SZs, however, this effect is
attenuated. This apparent impairment of normal habitua-
tion in schizophrenia could potentially be related, at least
in part, to a disruption of normal information processing
w141x in SZ which would require a balance between gluta-
matergic excitation and GABAergic inhibition.
An example of such information processing can be
found in the hippocampal CA subfields containing so-called
‘place’ cells that can be recorded from in awake, freely
moving rats w177x. Under normal conditions, the ‘place’
cells show a marked degree of plasticity while the rat is
performing a spatial working memory task in which stim-
uli in the surrounding field are moved w62x. GABAergic
neurons are known to play an active role in the processing
of information that takes place during spatial-temporal
memory encoding and retrieval w127x. It seems likely that
the ability of neuronal ensembles within the hipppocampus
to participate in such tasks would be markedly disturbed
by alterations of the GABA and glutamate systems similar
to those that have been detected in this region of
schizophrenic subjects. Consistent with this idea, a recent
study in which PET scanning was employed to study
hippocampal activation in schizophrenic subjects has
demonstrated a defect during retrieval of non-encoded
material w83x. Interestingly, the metabolic rate in the hip-
pocampus of these schizophrenics was increased at base-
line and this is consistent with the predictions derived from
the hypothetical models shown in Figs. 2 and 4. In both
models, an increased flow of activity along the trisynaptic
pathway has been postulated to occur in the hippocampal
formation of schizophrenics.
Another general area in which schizophrenic patients
show a marked functional impairment is attention w118x.
These patients lack the ability to filter out extraneous
information w49,128x and distinguish relevant from irrele-
vant objects in the perceptual field w113x. The anterior
cingulate cortex is an integral part of the so-called anterior
attentional system w133x and this has been found to play a
central role in such selective perceptual responses w125x.
Since this system does not appear to be functioning nor-
mally in schizophrenia w132x, altered neural circuitry within
the anterior cingulate region, like that shown in Figs. 1 and
2, could theoretically play a contributory role in the abnor-
malities of selective attention observed in this disorder.
261
Taking together the structural and functional observa-
tions in both the hippocampal formation and anterior cin-
gulate cortex in schizophrenic subjects, the altered macro-
circuitry postulated to be present in the limbic lobe could
potentially help to explain the abnormalities in information
processing and attention that are core features of this
disorder w39x.
2.5. Are the circuitry changes detected specific to
schizophrenia?
A critical issue that faces all postmortem studies of
schizophrenia is whether the changes noted are related
intrinsically to the disorder or whether perhaps they are
also seen in other psychoses and possibly represent the
non-specific effects of either stress or antipsychotic medi-
cation. In order to explore this question, recent studies
have been examining postmortem tissue from patients with
schizo-affective disorder and manic depression. For exam-
ple, in a cohort consisting of 15 normal controls, 15
schizophrenics and 9 manic depressives matched for age
and postmortem interval, the distribution of the GluR 5,6,7
subunit of the kainate receptor was assessed. The data have
shown a marked decrease of immunoreactive dendrites in
the schizophrenics, but not the manic depressive cases
when both were compared with a matched set of normal
controls w101x. This finding suggests that at least some
changes in the glutamate system may be specifically re-
lated to the pathophysiology of schizophrenia, but not that
of affective disorder.
In contrast, various markers for the GABA system have
not as yet shown such a clean segregation of findings
among various subtypes of major psychosis. For example,
the decreased density of nonpyramidal neurons discussed
above in an earlier section was most strikingly present in
schizophrenics with superimposed mood disturbances in
anterior cingulate cortex w22x. Most of these so-called
schizo-affective patients were treated with neuroleptic
medication and this factor could have contributed to this
finding. Another interpretation of these findings, however,
is that a loss of interneurons might show a stronger
covariation with affective disorder than with schizophre-
nia. As suspected, a more recent study has demonstrated
that manic depressive patients do indeed show a pro-
nounced reduction in the density of nonpyramidal neurons
in layer II of this region w172x. A subsequent meta-analysis
w27x in which the non-overlapping cases from three sepa-
rate studies w15,22,172x were combined was recently com-
pleted. The cases in this meta-analysis included 32 normal
controls, 17 schizophrenics without superimposed mood
disturbance, 18 schizo-affectives and 12 manic depres-
sives. The results demonstrated that there was a gradient in
the decreased density of nonpyramidal neurons in layer II
of the anterior cingulate cortex across the four groups:
manic depressives showed the largest change Ž40%.,
262 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
schizo-affectives the next largest Ž30%. and schizophrenics
without superimposed mood disturbances the smallest
change Ž15%.. In the hippocampal formation, a recent
report has also noted a decrease in the density of nonpyra-
midal neurons in both schizophrenia and manic depressive
illness w20x. In this study, however, both groups showed
approximately a 35–40% decrease that occurred selec-
tively in sector CA2, whether or not the patients had been
treated with neuroleptic medication. At this juncture, it
appears that some histopathologic changes, like those re-
lated to the GABA system, may occur broadly in the major
psychoses, while others, perhaps those related to the gluta-
mate system, may be a selective feature of schizophrenia.
Recently, a ‘two factor’ model of schizophrenia w89,126x
has postulated that both a genetic w78,94,97,98x and an
environmental risk factor have been invoked to explain the
occurrence of this disorder. Family studies of the psychotic
disorders have demonstrated two basic patterns of inheri-
tance. On the one hand, schizo-affective patients show
both affective disorder and schizophrenia among their
family members w69,105x, while, on the other, those with
schizophrenia tend to show the schizotypal personality
disorder in their first-degree relatives w94x. Schizo-affective
patients could be a genetically heterogeneous group of
patients who carry the genes for both schizophrenia and
affective disorder w105x, while these latter two disorders
may each reflect two distinct patterns of inheritance. An
important question to ask is whether any of the post-
mortem findings reported to date might reflect a suscepti-
bility gene specific to one or the other disorder.
Among potential environment risk factors, obstetrical
complications have been found to occur with considerable
frequency in the birthing records of patients not only with
schizophrenia w89,126x, but also with manic depressive
illness, particularly those with chronic psychotic features
w99x. As discussed above, however, non-specific stress
during the prodrome of the illness, and perhaps even later,
could play a role in the induction of histopathologic changes
in the brain. Based on these considerations, one could
postulate that histopathologic changes seen in both
schizophrenia and affective disorder could potentially be
related to a non-specific factor that is common to both
disorders, while those that occur in only one disorder, but
not the other, might reflect the presence of a specific
susceptibility gene w10x. Some of the findings related to the
GABA system Že.g., decreased density of nonpyramidal
cells. found in both schizophrenia and manic depressive
illness and could be related to an acquired risk factor. In
contrast, a change in the glutamate system Žsuch as a
decrease of GluR 5,6,7-IR dendrites in the hippocampus.
found only in schizophrenia could potentially reflect the
presence of a susceptibility gene for this disorder.
If this line of reasoning is correct, a change in the
glutamate system similar to that seen in schizophrenics
might be expected to occur in their first degree relatives,
while changes in the GABA system might not be detected
in their family members. To make distinctions of this type,
it will be imperative that first degree relatives of
schizophrenics and manic depressives be included in the
design of future postmortem studies so that this hypothesis
can be tested w7x.
2.6. How could normal deÕelopment ‘trigger’ the onset of
schizophrenia?
It is well-known that schizophrenia has a characteristic
age of onset between 16 and 25 years w102x. In considering
the significance of this observation, there is an inescapable
question that must be considered: Are there normal ontoge-
netic changes that are occurring in the brain during late
adolescence and early adulthood that may establish a
‘permissive’ environment for the onset of schizophrenia
w7x? Consistent with this hypothesis, a preliminary study
has demonstrated an increase in myelination in the supe-
rior medullary lamina along the surface of the medial
temporal lobe w8x. This finding was later replicated in a
much larger sample consisting of tissue from 163 normal
individuals processed and stained in an entirely different
manner w28x. In this latter study, a 100% increase of
myelin staining during the second decade of life was
detected in the superior medullary lamina which contains
projection fibers of the cingulum bundle and perforant
path. In other words, key corticolimbic afferent systems
projecting into the hippocampal formation appear to be
actively maturing during adolescence when the
schizophrenic phenotype becomes manifest. Such a devel-
opmental change must be considered as a potential ‘tri-
gger’ for the start of the schizophrenic syndrome, particu-
larly since the cingulum bundle is a key link between the
cingulate gyrus and hippocampal formation.
Other normal developmental changes that have been
reported to occur in humans during adolescence involve
synaptic density. For example, there is significant pruning
of synapses in the cerebral cortex during the first and
second decades of life w87x. Some believe that excessive
pruning during adolescence may be the proximate cause
for the start of schizophrenia w67x. Since the brain is not
shrinking during adolescence, in spite of the retraction of
synapses, it seems logical to conclude that other neuronal
elements must be filling the space left behind. One poten-
tially important change for the start of schizophrenia in-
volves the cortical dopamine projection. Several studies
have suggested that this system is undergoing a progres-
sive ingrowth during postnatal development w92,168x. This
normal infiltration of the cortex by dopamine fibers seems
to continue at least until the start of the early adult period
w92,168x and is associated with an increased interaction of
these fibers with both pyramidal and nonpyramidal neu-
rons w32x. Not surprisingly, when a double immunolocal-
ization procedure was employed, this interaction was found
to be specifically increased with respect to GABAergic
interneurons w32x. If dopamine acts as an inhibitory neuro-
 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
modulator, an increased interaction of these fibers with
GABA cells could theoretically result in a decompensation
of these latter neurons Žsee Fig. 1., particularly if, as
postulated above, GABA cells are defective in schizophre-
nia and other major psychoses. In this setting, a significant
decompensation of the intrinsic circuitry within layer II of
the anterior cingulate region could occur, especially under
stressful conditions when a marked increase in the release
of dopamine is known to occur in the cortex w140,163x.
Thus, if a similar phenomenon occurs in the human brain,
the continued ingrowth of the cortical dopamine system
during adolescence could contribute to the beginning of
the schizophrenic prodrome, particularly when associated
with stressful conditions.
Could a ‘mis-wiring’ of dopamine fibers with GABA
w26x cells appear de novo during adolescence as
schizophrenia is becoming manifest w14x? In a series of
experiments that were designed to address this issue, rats
were exposed to stress-simulating doses of corticosterone
during the pre- and post-natal periods. Those rats exposed
to corticosterone both pre- and postnatally showed an
increase in the number of dopamine varicosities forming
appositions with nonpyramidal cell bodies w14x. In contrast,
those rats exposed to glucocorticoid only during the post-
natal period did not show this change. Direct effects of
steroids on the expression of mRNA for TH w88,155,156x
could play a role in the induction of these changes during
the postweanling and early adult periods. Interestingly, rats
exposed prenatally to stress show persistently high levels
of activity in the hypothalamo-pituitary axis w159x, as well
as a potentiated response to stress during the pubertal
period and later during adulthood w72x. Taken together,
prenatal exposure to stress appears to enhance the subse-
quent response to stress later during adulthood. In a circuit
where there is a pre-existing reduction of GABAergic
activity ŽFig. 1., perhaps one related to obstretical compli-
cations w14x, the formation of superabundant connections
between dopamine fibers and an impaired population of
interneurons could lead to even further decreases of in-
hibitory modulation of pyramidal neurons by GABAergic
cells. Under stressful conditions, this latter scenario would
likely be associated with a severe decompensation in the
activity of the circuit shown in Fig. 1.
Another issue of importance with regard to the late
maturation of the dopamine system is whether it interacts
with serotonergic projections to the cortex because this
latter system also plays a role in mediating the effect of
neuroleptic medication. Since the serotonin system is be-
lieved to act as a neurotrophic factor in promoting the
ingrowth of thalamocortical afferents into the visual cortex
w56x, it seems plausible that it might also help to promote
the ingrowth of dopamine fibers during early adulthood. In
rats receiving lesions of the dorsal raphe nucleus during
the neonatal period, there is a marked decrease of the
serotonergic innervation in the medial prefrontal cortex
during adulthood. Dopamine fibers in these same rats show
263
a marked increase in density in the anterior cingulate
cortex of adults w160x and this suggests that the cortical
dopamine and serotonin systems may compete with one
another for functional space on cortical neurons. Since
there is both electrophysiological w74x and microscopic
w161x evidence for a convergence of dopamine and sero-
tonin projections onto individual cortical GABA neurons,
it seems reasonable to assume that an anomalous ingrowth
of dopamine fibers into the anterior cingulate cortex during
adolescence Žsee Section 2.2.3.. could be associated with
alterations in the serotoninergic projections as well.
3. Conclusions
The above discussion demonstrates that there has been a
reasonable degree of progress for our understanding of
how the neural circuitry may be altered within the limbic
lobe in schizophrenia. By bringing together the findings
for both the anterior cingulate cortex and hippocampal
formation, several principles may be derived regarding the
manner in which this circuitry is altered in the brains of
subjects with schizophrenia. These principles are as fol-
lows:
1. Schizophrenia is not a ‘typical’ degeneratiÕe disor-
der, but rather it is one in which a subtle form of excitotox-
icity may contribute to neuronal pathology. The fact that
necrotic cell death has been definitively ruled out as
playing a significant role in the pathophysiology of
schizophrenia has been a necessary step for this field, but
one that leaves a residual question as to why there is
atrophy and neuronal loss in some patients. Both of these
latter changes could potentially be related to an excitotoxic
mechanism: if occurring in a very severe form, it could
result in cell death, or alternatively, if occurring in a less
severe form it could be associated with cellular dysfunc-
tion, but not death. Neurons that fall victim to sustained
oxidative stress could show abnormal functioning that
disturbs the integrity of an entire circuit.
2. Three or more neurotransmitter systems may be
simultaneously altered in a single microcircuit within the
corticolimbic region. Data from several studies have sug-
gested that the glutamate, GABA and dopamine systems
may all be altered in layer II of the anterior cingulate
cortex. It seems likely that perhaps three or perhaps even
more transmitters may be simultaneously changed in a
single corticolimbic circuit of schizophrenic brain. Deter-
mining how each of these transmitter systems are interact-
ing with one another to generate anomalous behavioral
outputs in schizophrenia will be one of the great chal-
lenges facing this area of investigation. A serious impedi-
ment to the progress of this research is the fact that only
one transmitter system can generally be analyzed at any
given time in studies of postmortem human brain. With
time, however, the availability of increasingly sophisti-
264 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
cated technologies will make it possible to routinely co-
localize two or even three transmitter markers within a
single neural circuit in postmortem human brain.
3. One transmitter system may be altered in more than
one region, but may show different microcircuitry changes
in each. In the anterior cingulate and prefrontal cortices, as
well as sector CA1, the GABA A receptor appears to be
up-regulated on pyramidal neurons and this is consistent
with there being a decrease of classical inhibitory modula-
tion in these regions. In sector CA3, however, this receptor
binding activity is increased on nonpyramidal neurons, a
pattern suggesting that there may be a decrease of disin-
hibitory GABA modulation in this subfield. Based on these
observations, it is reasonable to conclude that it may not be
appropriate to assume that changes seen in one region may
be similar in other regions as well. When the cyto-archi-
tectonics and connectivity of two or more regions are
similar, then the pattern of results may be similar; how-
ever, when the intrinsic organization of a region, like the
hippocampus, shows unique features, then the circuitry
changes may not be predictable based on observations
elsewhere.
4. Both macrocircuitry and microcircuitry in the limbic
lobe are probably altered in schizophrenia. Examples of
discrete microcircuitry changes are those seen in layer II in
the anterior cingulate cortex ŽFig. 1. or hippocampus ŽFig.
3.. The presence of such changes implies that the commu-
nication between these adjoining regions could be func-
tionally altered Že.g., see as shown in Fig. 2. and impact on
the behavioral output of this complex network. In addition,
there may also be structural changes in the afferent inputs
Že.g., projections from the amygdala. that are received by
corticolimbic regions, such as the anterior cingulate cortex
and hippocampus. The methods available for studying such
connectivity in human brain are very limited; but, carefully
thought-out animal modelling can provide a constructive
way of gaining further insight into the nature of these
network changes. Using a coordinated approach in which
both human and animal studies are conducted in parallel, it
will be possible to gradually determine how the various
components of the corticolimbic system are altered in
schizophrenia.
5. Some changes are selectiÕely present in schizophre-
nia, while others appear to be also present in bipolar
disorder. The specificity of histopathologic changes in
schizophrenia is a critical issue. For example, a change of
the GluR 5,6,7 subunit have been preferentially found in the
hippocampus of schizophrenics, but not manic depressives.
In contrast, a variety of changes related to the GABA
system found in schizophrenics are also present in manic
depressives. An initial impression from these studies is that
abnormal GABAergic function may occur broadly across
the major psychoses and possibly reflect a common ac-
quired risk factor, while some alterations of the glutamate
system could be specific to schizophrenia and reflect the
presence of a susceptibility gene. The study of first degree
relatives will provide a critical strategy for distinguishing
between the effects of genes vs environment.
6. Some neural circuitry changes are related to neu-
roleptic drugs, but most are not. Although antipsychotic
medications have long been thought to be the cause of
most, if not all, changes observed in postmortem
schizophrenic brain, recent experience has challenged this
assumption. Several findings, such as the decreased den-
sity of nonpyramidal neurons, increased GABA A receptor
binding activity, increased density of vertical glutamate-
immunoreactive axons and decreased GluR 5,6,7 subunit are
present to a similar degree in patients with and without
neuroleptic exposure; however, others, such as the de-
creased density of TH-IR fibers and increase GAD65 -IR
terminals occur in neuroleptic-treated schizophrenics, but
not those who are drug-free. In the latter, case, neuroleptic
drugs may have obscured an intrinsic difference in the
distribution of GABA terminals. Support for this idea has
come from a study of neuroleptic effects in rats w169x.
Clearly, every parameter that is examined in postmortem
brain tissue must be separately evaluated for its relation-
ship to antipsychotic drug exposure.
7. Normal postnatal changes in the macro- and micro-
circuitry of the limbic lobe may serÕe as ‘triggers’ for the
onset of schizophrenia. To date, several different late
postnatal changes Že.g., increased myelination in the me-
dial temporal lobe and increased ingrowth of cortical
dopamine fibers. have presented themselves as potential
precipitants for the start of the schizophrenic syndrome. A
full characterization of such maturational changes at the
cellular and molecular level during adolescence and early
adulthood will point the way toward novel treatment strate-
gies, that can be applied early in the course of the illness.
In this way, it may eventually be possible to avert the
deterioration in functioning that typically occurs in many
patients with schizophrenia.
In the years to come, there will undoubtedly be many
more ‘principles’ that will become apparent as postmortem
studies of neural circuitry in schizophrenic brain continue
to progress. Hopefully, these principles that have emerged
early will help provide a framework for studies of this
type.
Acknowledgements
The author would like to thank all of the members of
the Laboratory for Structural Neuroscience who have made
this work possible. These individuals include: Jessica
Davidson, M.D., Ronald Maiccha, Ph. D., Micky Taleas,
Mary Turtle, Jennifer McSparren, John Paul Sangiovanni,
Stephen Vincent, Ph.D., Ingrid Sorensen, Raymond Mol-
loy, Yusuf Khan, Ariel Marie-Snyder, Mark Todtenkopf,
Patti Fitzpatrick, Jill Bolte Taylor, Ph.D., Esther Kwok,
Stephanie Davidoff, M.D., Ph.D., Paul Kostaloukos and
Sabina Berretta, M.D. The author is also grateful to Drs.
 F.M. Benes r Brain Research ReÕiews 31 (2000) 251–269
Alfred Pope and Steven Matthysse who spent many hours
discussing microscopic analysis of postmortem human
brain. Special thanks goes to Maureen Medeiros for her
help in preparing this manuscript. This work was sup-
ported by grants from the National Institutes of Health
ŽMH00423, MH42261, MH31152, MHrNS31862., the
Scottish Rite Foundation and the Stanley Foundation.
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