Brain Research Reviews 31 Ž2000.

138–146
www.elsevier.comrlocaterbres

Interactive report

Evidence for a compromised dorsolateral prefrontal cortical parallel

circuit in schizophrenia 1
William E. Bunney ) , Blynn G. Bunney
Department of Psychiatry, College of Medicine, UniÕersity of California, IrÕine, Med Sci I, Room D440, IrÕine, CA 92697, USA
Accepted 30 June 1999

Abstract

Evidence is reviewed that one of the cognitive-affective parallel circuits in the brain, the dorsolateral prefrontal circuit, is
compromised at the level of anatomical, neuropathological and transmitter-related molecules in a subgroup of schizophrenic patients. The
dorsolateral prefrontal cortex ŽDLPFC. comprises a key structure in this circuit. Data supporting a compromised DLPFC includes
cognitive deficits, decreased regional metabolism and blood flow activation; disruption of cortical subplate activity Žinferred from
maldistribution of neurons from the cortical subplate which are required for the orderly neuronal migration during the second trimester
and for connectivity of the thalamocortical neurons.; decrease in major components of the cortical inhibitory neurotransmitter system; and
alterations in the molecules critical for NMDA-receptor mediated neural transmission. Thus a great deal of evidence accumulated over the
last decade has definitively implicated the dorsolateral prefrontal cortex in the pathophysiology of schizophrenia. Emerging data also
confirms neuropathology in the mediodorsal nucleus of the thalamus that projects to the DLPFC. There is currently a consensus that
schizophrenia involves epigenetic factors interacting with genetic information in the cells to produce abnormal molecules which when
they are associated with abnormal circuits such as the DLPFC, may result in abnormal behavior. Thus, abnormal cortical connections and
or altered neurotransmitter related molecules in the DLPFC could explain some of the prominent frontal cognitive disruptions seen in
schizophrenia. q 2000 Elsevier Science B.V. All rights reserved.

Keywords: Schizophrenia; Dorsolateral prefrontal cortex; Neurodevelopmental disorder

Contents

1. Introduction . ....................................................................... 139

2. Defective cognitive functioning in schizophrenia associated with the prefrontal cortex including the DLPFC .................... 139

3. Metabolism, cerebral blood flow activity, and cognitive functioning .......................................... 139

4. Hypofrontality in schizophrenia ............................................................. 140

5. Neurodevelopmental defects and a window of vulnerability in the second trimester of pregnancy . .......................... 140

6. Postmortem findings in prefrontal cortical areas of schizophrenics ........................................... 140

7. Cognitive affective parallel circuits ........................................................... 141

8. Cortical subplate ..................................................................... 141

)
Corresponding author. Tel.: q1-949-824-4242; Fax: q1-949-824-1787; E-mail: webunney@uci.edu
1
Published on the World Wide Web on 10 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 3 1 - 4
 W.E. Bunney, B.G. Bunneyr Brain Research ReÕiews 31 (2000) 138–146
9. Cytoarchitectural alterations in dorsolateral prefrontal cortex .
10. Abnormalities of neurotransmitter-related molecules in the DLPFC of schizophrenic patients
References ..........................................................................
1. Introduction
This paper will review evidence that one of the cogni-
tive-affective parallel circuits in the brain, the dorsolateral
prefrontal circuit, is compromised at the level of anatomi-
cal, neuropathological and transmitter-related molecules in
a subgroup of schizophrenic patients. These compromised
systems may explain some of the prominent prefrontal
cognitive deficits seen in schizophrenia. A great deal of
accumulated evidence over the last decade has definitively
implicated the dorsolateral prefrontal cortex ŽDLPFC. in
the neuropathology of schizophrenia. Emerging data also
confirms neuropathology in the mediodorsal nucleus of the
thalamus that projects to the DLPFC. There is currently a
consensus that schizophrenia involves epigenetic factors
interacting with genetic information in the cells to produce
abnormal molecules which when they are associated with
abnormal circuits such as the DLPFC, may result in abnor-
mal behavior. A review of evidence at various levels
including cognitive, neuropsychological testing, neu-
roimaging, cytoarchitectural and neurotransmitter-related
molecules supports a contributing role of the DLPFC to
schizophrenia.
2. Defective cognitive functioning in schizophrenia asso-
ciated with the prefrontal cortex including the DLPFC
Although schizophrenia is a heterogeneous illness, there
is a commonality in that most patients perform poorly on
cognitive tasks that require intact prefrontal functioning. It
is well-documented that schizophrenics have difficulty with
the Wisconsin Card Sort Task ŽWCS., a task requiring
skills for abstract reasoning, problem solving and working
memory Žsee w1x for review.. Some of the most convincing
data comes from investigations of monozygotic twin pairs
discordant for schizophrenia. Comparisons of well twins,
with their ill twin counterparts show that the affected twins
have significantly lower WCS scores w2x. Deficits on tests
such as visuospatial tasks w3x and auditory letter-number
spans w4x requiring working memory skills have been
reported in schizophrenia even though perceptual abilities
may be intact w3x. Goldman-Rakic and Selemon w5x con-
clude from data in animal and clinical studies that intact
prefrontal cortical circuitry is required to modulate work-
ing memory which may relate to the cognitive deficits in
schizophrenia. The relationship between cognitive deficits
139
............................................. 142
............................ 142
143
with DLPFC activation provides further insight into DLPFC
circuitry function as reviewed below.
3. Metabolism, cerebral blood flow activity, and cogni-
tive functioning
Experimental paradigms integrating neuropsychological
testing with data from neuroimaging techniques Že.g., PET,
133-xenon rCBF, SPECT and fMRI. provide evidence that
schizophrenics have deficits in DLPFC activation. Perfor-
mance of the WCS by normal controls, for example, is
associated with an increase in prefrontal activation includ-
ing the DLPFC. In contrast, schizophrenics taking the
WCS, initially show DLPFC activation that deteriorates as
the task demands increase. Blood flow studies of monozy-
gotic twins discordant for schizophrenia reveal that during
the WCS task, the prefrontal blood flow index Žthe ratio of
prefrontal rCBF flow to non-frontal flow expressed as a
percentage. is decreased in the schizophrenic twins. Re-
ductions in DLPFC blood flow activation are present in
acute, chronic w1x, neuroleptic-naıve ¨ w6x and medicated
patients w1x. The administration of two cognitive tasks, the
PART ŽPaired Associate Recognition Task., a task testing
declarative memory, and the WCS showed that although
schizophrenics performed poorly on both, DLPFC activa-
tion was only compromised during performance of the
WCS w7x.
Data from oxygen-15 PET and fMRI studies suggest a
relationship in changes in DLPFC activation as a function
of increasing task demands. Results from studies of graded
memory tasks show that schizophrenics, similar to nor-
mals, initially have increases in DLPFC activity during test
performance, however, as task demands increase, DLPFC
activity begins to deteriorate and falls significantly below
that of controls w8x. Carter et al. w9x reported similar results
in a PET study using the ‘N-back’ task, a cognitive test
known to activate the prefrontal cortex in normal subjects.
Results from this study showed decreased activation in the
right DLPFC in schizophrenics in response to increased
difficulty. Data from an fMRI study using the ‘N-back
task’ similarly showed a deficit in DLPFC activity in
schizophrenics w10x. Attenuated frontal activation in
schizophrenics was also observed in an fMRI study utiliz-
ing a verbal fluency task of silent word generation in
response to a verbal letter cue. In contrast to controls,
patients had attenuated frontal activation in the left DLPFC
140 W.E. Bunney, B.G. Bunneyr Brain Research ReÕiews 31 (2000) 138–146
w11x. Additional and potentially complicating reports of
decreased DLPFC activation in schizophrenics compared
to controls are seen in an 15-oxygen PET study of DLPFC
activation in response to joystick movement w12x.
4. Hypofrontality in schizophrenia
Brain imaging data collected over more than two
decades strongly supports a decrease in frontal lobe activa-
tion Žhypofrontality. in a significant subgroup of schizo-
phrenics as compared to controls, including regions involv-
ing the DLPFC Žsee reviews w13,14x.. A wide variety of
neuroimaging techniques have been used to assess DLPFC
function with 133-xenon rCBF w15x and SPECT ŽTc99m-
HMPAO. w16x and with 15-oxygen PET w7–9,12,17x and
functional MRI ŽfMRI. w11,18–20x which report hy-
pofrontality in schizophrenic cohorts as compared to con-
trols. Hypofrontality is observed in patients that are neu-
¨ w21–24x in patients off-medications w25x, as
roleptic-naıve
well as in adolescent patients with childhood onset schizo-
phrenia w26x.
Deficits in prefrontal regions of schizophrenics can be
visualized with 31 P magnetic resonance spectroscopy
ŽfMRS. w27x and with proton magnetic resonance spectro-
scopic imaging Ž 1 H-MRSI. w20,28x Bertolino w20x observed
that adolescents with childhood-onset schizophrenia as well
as adult-onset schizophrenia patients had significantly
lower metabolite peaks of the proton spectra Ži.e., N-acetyl
aspartate ŽNAA.rcreatine ratios. in the DLPFC suggestive
of neuronal damage or malfunction. Another study from
the same laboratory w28x reported significant reductions in
NAArcreatine and NAArcholine ratios in the DLPFC of
a group of 12 untreated schizophrenic patients Ž5 neurolep-
¨ and 7 medication-free patients..
tic-naıve
MRI technology, used to quantify gray and white matter
changes in prefrontal tissue of schizophrenics, report that
schizophrenics as compared to controls have decreased
prefrontal gray matter volumes w30–32x, a finding which is
also observed in first-episode schizophrenics w33x. Reduc-
tions in prefrontal white matter volume although reported
w29,32x are not consistently observed Že.g., w34,35,37x.. An
attempt to correlate gray and white matter volumes with
metabolic deficits Žphosphomonoesters. using 31 P MRS in
schizophrenics failed to show a relationship w27x.
Employing a new application of MRI to study schizo-
phrenia, Buchsbaum et al. w36x used diffusion tensor imag-
ing, a technology that allows direct assessment of the large
axon masses stretching from the prefrontal cortex to the
striatum. Five patients with schizophrenia and six age- and
gender-matched normal controls were studied with diffu-
sion tensor images, high resolution structural MRI and
FDG-PET techniques. Compared to controls, schizophren-
ics had lower diffusion anistropy in white matter regions
of the prefrontal cortex. The investigators concluded that
these results provide evidence for diminished frontal-striatal
connectivity in schizophrenia.
5. Neurodevelopmental defects and a window of vulner-
ability in the second trimester of pregnancy
Studies of pregnant mothers exposed to trauma Že.g.,
viral infection, malnutrition, stress. provides data relevant
to the understanding of schizophrenia Žsee w37x for review..
Data from these studies suggest that there is a period of
‘ vulnerability’ during which the fetus may be placed at a
higher risk for schizophrenia. A critical period of time
appears to be in the second trimester which coincides with
a massive neuronal migration of cells from the inner
ventricular zone to form the outer layers of the cortex in
the human brain. During this period, it is hypothesized that
the developing brain may be vulnerable to epigenetic
traumatic events, specifically if there are underlying ge-
netic predisposing factors.
Data from medical records during the Helsinki in-
fluenza A2 virus in 1957, led Mednick et al. w38x to
develop the hypothesis that mothers exposed to the virus
during the second in contrast to the first and third trimesters
were at higher risk for having offspring that would later
develop schizophrenia. More than 15 studies have since
replicated these findings in other countries including Edin-
burgh, England and Wales, Tokyo and Ireland. Each of
these has suggested that the second trimester of pregnancy
is a window of vulnerability although as reviewed by
Mednick et al. w34x some investigators failed to replicate
these results. Second trimester effects were not found in
studies of influenza epidemics in Western Australia w39x
nor in a population of Caribbean immigrants to Europe
having an increased rate for schizophrenia w40x. It is impor-
tant to note that although viral studies may help us desig-
nate a window of vulnerability, they are clearly not an
etiological factor in most cases in schizophrenia. Other
studies implicate severe psychological stress w41,42x and
malnutrition w43x as factors that can influence the incidence
of schizophrenia in developing offspring.
6. Postmortem findings in prefrontal cortical areas of
schizophrenics
Research investigations of postmortem tissue has yielded
a wealth of data suggesting that the schizophrenic brain
may be differentiated from controls in terms of neuronal
density, neuronal cell settling patterns, as well as in the
gene expression of neuronal transmitter-related molecules,
particularly in prefrontal cortical regions. Analyses of neu-
ronal density changes in the prefrontal cortical areas of the
schizophrenic brain show decreases in neuronal density in
Layer VI w44x; decreases in interneuronal density in layer
II and to a lesser extent in Layer I w46x; reductions in
 W.E. Bunney, B.G. Bunneyr Brain Research ReÕiews 31 (2000) 138–146
neuronal size and increases in density of small neurons in
prefrontal regions w47,48x and increased overall neuronal
density in layer VI Ž3D counting method. of area 9 w49x
and in area 46 in layers II, III, IV, and VI w50x. Although
neuronal alterations are frequently associated with the
prefrontal cortical areas of the schizophrenic brain, there is
a relative absence of neuropathological changes consistent
with neurodegenerative processes w47x.
7. Cognitive affective parallel circuits
Fig. 1 represents a redrawing from Alexander, DeLong
and Strick’s paper w51x defining 3 parallel circuits which
relate to cognitive affective components. The dorsolateral
prefrontal cortex circuit involves the DLPFC in the cortex,
the dorsolateral caudate nucleus of the striatum, the lateral
dorsal medial nucleus of the globus pallidus, the postero-
lateral nucleus of the substantia nigra and the ventral
anterior, medial dorsalis, pars parvocellularis subnuclei of
the dorsal medial nucleus of the thalamus. Defects in any
of these structures could produce alterations in intrinsic-
and extrinsic-functional connectivity that may be related to
symptoms of schizophrenia. There is preliminary evidence
to suggest deficits in the dorsal medial thalamic nuclei
w52–55x which have extensive connections with the DLPFC
are present in schizophrenics. Data from a 1 H-magnetic
resonance spectroscopy study of 8 schizophrenics and 10
controls revealed a non-significant trend of reductions in
Fig. 1. Dorsolateral prefrontal cortical parallel circuit in schizophrenia.
141
NAA, glutamate and valine in the thalamus of the
schizophrenic group w56x. Additionally, evidence from
magnetic resonance imaging shows significantly different
correlations between thalamic volumes with prefrontal
white matter among chronic male schizophrenics but not
among controls w23x. Thalamic volumes among patients
were significantly correlated with clinical symptoms such
as bizarre behavior, hallucinations and thought disorder
w57x although Wolkin et al. w58x using MRI techniques,
reported no differences within the thalamus.
8. Cortical subplate
The cortical subplate is a transitory neuronal structure
laid down in the beginning of the second trimester, reach-
ing maximum peak in the early third trimester w59x. Most
subplate cells undergo programmed cell death during the
late fetal and early postnatal life although tens of thou-
sands remain in the adult brain as interstitial neurons of
white matter w59x. The subplate may function as a cellular
scaffold, a critical but transitory link between the cortical
target cells and thalamic axons w60x. Lesions studies in cats
have shown that subplate neurons are required throughout
the neocortex in the process of cortical target selection
w60x. Thus remnants of the subplate provide a marker
which could allow one to evaluate in postmortem tissue a
critical second trimester developmental process in the brain.
Abnormal cell settling patterns of these subplate neurons
142 W.E. Bunney, B.G. Bunneyr Brain Research ReÕiews 31 (2000) 138–146
offer a unique window and marker to identify early neu-
rodevelopmental pathology.
9. Cytoarchitectural alterations in dorsolateral pre-
frontal cortex
Anatomical and epidemiological studies support the
hypothesis that disturbances of orderly brain development
may contribute to the etiology of schizophrenia. Findings
suggest that abnormal patterns of neuronal migration dur-
ing the development of the cerebral cortex may be in-
volved in schizophrenia providing evidence that cortical
connectivity and associative function could be disturbed. A
test of this hypothesis focused on the quantification of
NADPH-d Žnicotinamide-adenine dinucleotide phosphate
diaphorase.-labeled cells in the white matter of the brain of
schizophrenics and matched controls. NADPH-d stained
cells are found in the non-pyramidal cells of the DLPFC
and provide a marker for the remnants of the cortical
subplate. These cells represent a subpopulation of neurons
that remain in the brain throughout adulthood. The cells
are particularly resistant to neurodegenerative processes.
NADPH-d is the enzyme which catalyses the reaction of
adenine to the free radical nitric oxide ŽNO.. NADPH-d
containing cells appear to be protected from the effects of
nitric oxide released under neurotoxic conditions w61x. An
early study in our laboratory w62x evaluated NADPH-d
stained cells in the prefrontal cortex and underlying white
matter. The methodology in these studies involve immuno-
histochemistry, densitometry and quantified cell counting
methods. In the normal brains, these neurons are found in
the largest numbers in the white matter immediately deep
to layer 6 of the cortex where they remain from the
subplate. The DLPFC of the schizophrenic patients showed
a significant decrease in NADPH-d labeled neurons in the
superficial white matter and in the overlying cortex while
they show a significant increase in these stained neurons in
white matter deeper than 3 mm from the cortex. These
findings are consistent with a disturbance of the cortex
during development. It is unlikely that neuroleptic treat-
ment affected these neurochemically and functionally ho-
mogenous neurons in a different way in the cortex and
white matter. One of the most severe cases had not been
treated with neuroleptics therefore a drug-related cause is
unlikely. A subsequent study evaluated NADPH-d stained
neurons in the lateral and medial temporal lobes of
schizophrenic and matched control brain tissue. The find-
ings were similar to those shown in the frontal lobe with
the schizophrenics having significantly lower NADPH-d
stained neurons in the outer layers of the hippocampal
formation and in the neocortex of the lateral temporal lobe
were observed while significantly greater numbers in the
NADPH-d stained neurons in the white matter of the
lateral temporal lobe with a tendency toward increased
numbers in the parahippocampal white matter w63x. Thus,
changes in cortical ontogenesis as reflected in the distur-
bance of NADPH-d-stained neurons may be widespread
among neocortical association fields in schizophrenics.
NADPH-d positive neurons represent only a small sub-
set of cortical subplate cells. Additional markers include
MAP-2, microtubular-associated proteins representing the
largest fraction of subplate neurons, and SMI-32, a mono-
clonal antibody which represents a non-phosphorylated
neurofilament protein Ž160–200 kDA.. Together these three
markers label approximately 85% of subplate cells. Utiliz-
ing these neuronal markers, we observed a maldistribution
of all three populations of interstitial neurons in the middle
frontal gyrus of schizophrenics compared to matched con-
trols. For each neuronal population there was a significant
increase in the density of neurons toward the deeper white
matter. Thirty-five percent of the 20 schizophrenic brains
investigated in this study but no brains of the 20 control
subjects showed a maldistribution of neurons toward deeper
white matter with at least two of the three markers.
Selective displacement of interstitial white matter neurons
in the frontal lobe in the DLPFC may indicate alterations
in neuronal migration possibly leading to defective cortical
circuitry in the brains of schizophrenic patients w64x. An-
derson et al. w65x evaluated MAP-2 in 5 schizophrenic
cases and matched controls. Although their findings dif-
fered from those reported, they concluded that the results
of both investigations agreed on a common hypothesis that
prefrontal cortical dysfunction in schizophrenia may be a
later consequence of an early developmental disturbance in
the organization of the cortical subplate w65x. These find-
ings may represent some of the most direct evidence for a
neurodevelopmental defect in schizophrenia.
10. Abnormalities of neurotransmitter-related
molecules in the DLPFC of schizophrenic patients
The major inhibitory neurotransmitter of the brain,
gamma-aminobutyric acid ŽGABA . is altered in
schizophrenia as shown by decreases in GABA release and
uptake w66–68x and reductions in the density of GABA
axon terminals w69x as compared to controls. Further re-
search revealed that the GABA-A receptor, a site of action
of psychotropic drugs is increased in schizophrenics as
compared to controls, particularly in layer II of the pre-
frontal cortex and the adjacent prefrontal cortex w44,45x.
Reductions in small interneurons in cortical layer 2, espe-
cially in brains of schizophrenic patients with affective
disturbances led Benes w46x to hypothesize alterations in
the GABA-ergic system. Daviss and Lewis w29x report an
increase in the density of local circuit neurons in the
prefrontal cortical areas of a subpopulation of GABA
neurons Žcalbindin-labeled neurons. by as much as 50–70%
in layers III, V, and VI of schizophrenics compared to
controls matched for age, gender and autolysis time. How-
ever, analyses of mRNA levels for six GABA-A receptor
 W.E. Bunney, B.G. Bunneyr Brain Research ReÕiews 31 (2000) 138–146
subtypes Ž a1, a 2, a 5, b1, b2, g2. failed to support
significant changes in the prefrontal cortex of schizophren-
ics as compared to matched controls w75x.
Glutamic acid decarboxylase ŽGAD. is the key enzyme
in the synthesis of GABA in inhibitory interneurons. GAD
is regulated in an activity-dependent manner in the cere-
bral cortex of non-human primates w70,71x. Conduction
block of the optic nerve in adult monkeys causes a re-
versible decrease in immunoreactive GAD and GABA
levels w70,71x. A decrease in GABA immunoreactivity is
associated with decreased levels of GAD mRNA w48x
suggesting that the activity-dependent regulation of corti-
cal GABA may depend on the regulation of GAD gene
expression. Levels of messenger RNA for the 67 Kd
isoform of GAD and the number and laminar distribution
of GAD mRNA-expressing neurons in the DLPFC of
schizophrenics and matched controls were quantified using
in situ hybridization-histochemistry, densitometry and cell
counting methods. As a control, mRNA levels for type II
calcium-calmodulin-dependent protein kinase ŽCamIIK.
were also quantified. Schizophrenics showed a significant
decrease in GAD mRNA levels in neurons of layers I
Ž40%. and II Ž48%. and an overall 30% decrease in layers
III to VI while there were no significant differences in
CamIIK mRNA levels between the schizophrenic patients
and the controls. Prefrontal gray and white matter volumes
did not differ significantly nor were there differences
found in the total number of small, round or oval neurons
which should include most of the GABA cells w72x. The
reduced expression of GAD may be a result of an activity-
dependent down-regulation associated with the functional
hypoactivity of the DLPFC which has been documented
with PET scans. A strikingly similar finding has been
independently observed by Volk et al. w73x who also
reported that the gene expression for GAD is reduced in
layers I–V, most significantly in Layers III–IV, without
loss of neurons in the prefrontal cortex of schizophrenic
patients.
Perturbations in NMDA transmission are thought to be
a contributing factor in schizophrenia in view of the
observation that NMDA receptor antagonists can induce a
schizophrenic-like psychosis in normals w74x. Thus, the
evaluation of the gene expression for NMDA receptor
subunits in prefrontal cortex of schizophrenics as com-
pared to controls matched for age, gender and autolysis
time was undertaken w75x. Excitatory amino acid ionotropic
receptors can be divided into three categories: NMDA,
kainate, and AMPA. Further classifications include NM-
DAR1 Ž8 slice variants. and NMDAR2 ŽA–D., AMPA
ŽGluR1–4., and kainate-low affinity ŽGluR5–GluR7. and
kainate-high affinity ŽKA1–KA2. receptors. NMDA recep-
tors are comprised of heteromeric assemblies of subunits,
more specifically, NR1 subunits combine with different
NR2 subunits. Expression patterns of the mRNAs of the
five NMDA receptor subunits ŽNR1rNR2A–D. were de-
termined by in situ hybridization in prefrontal, parieto-tem-
143
poral and cerebellar cortex in brains of schizophrenics,
neuroleptic-treated and comparison patients, and matched
controls. Significant changes in the schizophrenic cohort
were observed only in the prefrontal cortex where there
was a shift in the relative proportion of mRNAs for NR2
subunit family with a 53% relative increase in the expres-
sion of the NR2D subunit mRNA. Similar changes were
not observed in neuroleptic-treated nor in untreated con-
trols. Regional heterogeneity of subunit expression in hu-
man cerebral and cerebellar cortex was found w76x. The
NR2D subunit of the NMDA receptor has the following
potential relevance. In cerebral cortex the expression of
NR2D subunit is developmentally regulated w77x and is
required to induce the formation of specific neuronal con-
nections w78–80x. Recombination experiments in cell cul-
ture demonstrate that NMDA receptors assembled from
NR1 and NR2D subunits show a prolonged decay rate of
glutamate-induced ion currents and a lowered threshold for
voltage-dependent Mg 2q blockade compared with NMDA
receptors assembled from NR1 and NR2A or NR2B sub-
units w77x. These specific kinetic properties of NMDA
receptors containing the NR2D polypeptide are thought to
ensure effective postsynaptic depolarization under condi-
tions when presynaptic activity is reduced w77x. The in-
creased proportion of this ‘hyperexcitable’ type of NMDA
receptor in the prefrontal cortex could be a significant
response to prefrontal hypoactivity in order to compensate
for a general reduction in neuronal activity w76x.
The DLPFC comprises a key structure in the dorsolat-
eral prefrontal circuit. In conclusion, evidence from di-
verse experimental investigations support a dysfunction in
the DLPFC in a subgroup of schizophrenics based on Ž1.
compromised cognitive functioning, Ž2. decreased regional
glucose metabolism and blood flow activation, Ž3. disrup-
tion of cortical subplate activity Žinferred from maldistribu-
tion of neurons from the former cortical subplate., disor-
dered connectivity in the frontal cortex Žthe subplate is
required for orderly migration during the second trimester
and for connectivity of the thalamacortical neurons. Ž4.
decrease in major components of the cortical inhibitory
neurotransmitter system Ž5. Alterations in the molecules
critical for NMDA-receptor mediated neural transmission.
Abnormal cortical connections andror altered neurotrans-
mitter-related molecules in the dorsolateral prefrontal corti-
cal circuit could explain some of the prominent frontal
cognitive disruptions seen in schizophrenia.
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