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Original Article |

Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia FREE

Leisa A. Glantz, PhD; David A. Lewis, MD
[+] Author Affiliations

From the Departments of Neuroscience (Drs Glantz and Lewis) and Psychiatry (Dr Lewis), University of Pittsburgh, Pittsburgh, Pa.


Arch Gen Psychiatry. 2000;57(1):65-73. doi:10.1001/archpsyc.57.1.65.
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Background  The pathophysiological characteristics of schizophrenia appear to involve altered synaptic connectivity in the dorsolateral prefrontal cortex. Given the central role that layer 3 pyramidal neurons play in corticocortical and thalamocortical connectivity, we hypothesized that the excitatory inputs to these neurons are altered in subjects with schizophrenia.

Methods  To test this hypothesis, we determined the density of dendritic spines, markers of excitatory inputs, on the basilar dendrites of Golgi-impregnated pyramidal neurons in the superficial and deep portions of layer 3 in the dorsolateral prefrontal cortex (area 46) and in layer 3 of the primary visual cortex (area 17) of 15 schizophrenic subjects, 15 normal control subjects, and 15 nonschizophrenic subjects with a psychiatric illness (referred to as psychiatric subjects).

Results  There was a significant effect of diagnosis on spine density only for deep layer 3 pyramidal neurons in area 46 (P = .006). In the schizophrenic subjects, spine density on these neurons was decreased by 23% and 16% compared with the normal control (P = .004) and psychiatric (P = .08) subjects, respectively. In contrast, spine density on neurons in superficial layer 3 in area 46 (P = .09) or in area 17 (P = .08) did not significantly differ across the 3 subject groups. Furthermore, spine density on deep layer 3 neurons in area 46 did not significantly (P = .81) differ between psychiatric subjects treated with antipsychotic agents and normal controls.

Conclusion  This region- and disease-specific decrease in dendritic spine density on dorsolateral prefrontal cortex layer 3 pyramidal cells is consistent with the hypothesis that the number of cortical and/or thalamic excitatory inputs to these neurons is altered in subjects with schizophrenia.

Figures in this Article

THE DORSOLATERAL prefrontal cortex (DLPFC) appears to be a critical site of dysfunction in subjects with schizophrenia. For example, schizophrenic subjects perform poorly on cognitive tasks that are subserved by DLPFC circuitry,1,2 and this performance deficit is correlated with diminished activation of the DLPFC.2,3

The results of structural imaging studies48 suggest that DLPFC dysfunction in subjects with schizophrenia may be related to a decreased volume of this brain region. Findings of increased cell packing density,911 without a change in neuronal number,12,13 suggest that this volume reduction may be due to a decreased amount of DLPFC neuropil in subjects with schizophrenia.14 Because the axon terminals and dendritic spines of the neuropil represent the major anatomical substrate for synapses, these findings suggest the presence of abnormalities in DLPFC connectivity in subjects with schizophrenia.

Consistent with this interpretation, magnetic resonance spectroscopic studies1518 have found decreased levels of N-acetylaspartate, a putative marker of neuronal and/or axonal integrity, in the DLPFC of schizophrenic subjects. Reports1921 of decreased phosphomonoesters, increased phosphodiesters, or both in the DLPFC of schizophrenic subjects have also been interpreted to reflect an increased breakdown of membrane phospholipids and, consequently, a decreased number of synapses.22 Finally, levels of synaptophysin, a presynaptic terminal protein, are decreased in the DLPFC of schizophrenic subjects.2326 Although other interpretations are possible, each of these findings supports the hypothesis that DLPFC synaptic number is diminished in subjects with schizophrenia.

Understanding the pathophysiological significance of such alterations requires knowledge of the types of synapses that are affected and of their postsynaptic targets. Several findings suggest that schizophrenia may be associated with abnormalities in the excitatory inputs to layer 3 pyramidal neurons in the DLPFC. For example, the basilar dendritic spines of pyramidal cells in deep layer 3 are likely targets of projections from the mediodorsal thalamic nucleus,27,28 and the number of neurons in this nucleus appears to be decreased in subjects with schizophrenia.2931 In addition, excitatory inputs to layer 3 pyramidal cells decline substantially in number during late adolescence,3234 the typical age when the clinical features of schizophrenia become manifest.

Consequently, the purpose of this study was to test the hypothesis that schizophrenia is associated with a diminished complement of excitatory synapses onto DLPFC layer 3 pyramidal neurons. Because dendritic spines are the principal site of excitatory inputs to pyramidal neurons,35 and reflect the number of these synapses,35,36 we quantified dendritic spine density on the basilar dendrites of layer 3 pyramidal neurons in schizophrenic subjects and 2 groups of comparison subjects.

SUBJECT CHARACTERISTICS

Specimens from 45 human brains were obtained during autopsies conducted at the Allegheny County Coroner's Office, Pittsburgh, Pa (Table 1). Informed consent for brain donation was obtained from the next of kin. Neuropathological abnormalities were detected in 6 subjects. Subject 517 had a vascular malformation and hemorrhage confined to the right temporal lobe, and subject 622 had an acute infarction limited to the distribution of the right middle cerebral artery. However, the cortical regions of interest for the present study were not affected in either subject. In 4 subjects (subjects 532, 564, 609, and 632), thioflavine S staining revealed a few senile plaques without any neurofibrillary tangles. The density of plaques was insufficient to meet the diagnostic criteria for Alzheimer disease,37 and there was no history of dementia in any subject.

Table Graphic Jump LocationTable 1. Characteristics of Control, Schizophrenic, and Psychiatric Subjectsa

Fifteen subjects with a diagnosis of schizophrenia or schizoaffective disorder were compared with 15 normal control subjects and 15 nonschizophrenic subjects with a psychiatric illness (referred to as psychiatric subjects) (Table 1). For each subject, an independent committee of experienced clinicians made consensus DSM-III-R38 diagnoses using information obtained from clinical records and structured interviews conducted with surviving relatives of the subject.23 One of the normal controls (subject 370) was later found to have a diagnosis of alcohol abuse, current at the time of death. Thirteen of the subjects in the psychiatric comparison group had a mood disorder, and 2 had other psychotic disorders. All of the schizophrenic subjects had a history of treatment with antipsychotic agents, and 9 of the psychiatric subjects had been treated with these medications. All procedures were approved by the Institutional Review Board for Biomedical Research at the University of Pittsburgh, Pittsburgh, Pa.

Subject groups did not differ significantly in sex, race, age, postmortem interval (PMI), tissue fixation time, or incidence of out-of-hospital deaths (Table 2). In addition, the schizophrenic and psychiatric subjects did not differ on the incidence of alcohol or other substance use disorders, mean age at onset of illness, or mean duration of illness. However, the number of deaths by suicide was significantly higher in the psychiatric subjects (Table 2).

Table Graphic Jump LocationTable 2. Summary of Subject Characteristics*
PREPARATION OF TISSUE

From the left hemisphere of each brain, tissue blocks were cut from standardized locations in the DLPFC and primary visual cortex, immersed in 4% paraformaldehyde for longer than 4 weeks, and then processed by a previously described modification39 of the rapid Golgi procedure.40 Sections were cut at 90 µm and mounted onto coded slides so that investigators were not aware of subject number or diagnosis.

Area 46 of the DLPFC and area 17, primary visual cortex, were examined in this study. Area 17 was not available for 2 schizophrenic subjects (subjects 410 and 622) and 1 psychiatric subject (subject 637). Nissl-stained sections from tissue blocks immediately adjacent to those used for the Golgi procedure were examined to confirm that the Golgi material contained the cytoarchitectural features of areas 46 or 17.9,41 The Nissl-stained sections were also used to determine the borders of layer 3 as a percentage of total cortical thickness. In area 46, the layer 2 to 3 border was located on average (±SD) 18.2% (±3.4%) and 20.8% (±2.8%) of the distance from the pial surface to the white matter for the schizophrenic and control subjects, respectively, and the layer 3 to 4 border was located at 53.6% (±3.1%) and 56.8% (±1.2%) of the total cortical thickness in these 2 subject groups, respectively. These findings are consistent with previous reports11,42 that the relative thicknesses of cortical layers are similar in schizophrenic and control subjects. Consequently, Golgi-impregnated neurons located between 20% and 55% of the distance from the pial surface to the white matter in area 46 were considered to be located in layer 3. In Golgi-processed sections containing area 17, a dark band demarcated layer 4.40 Therefore, sampled neurons were located superficially to this band or within 20% to 45% of the distance from the pial surface to the white matter.

NEURON RECONSTRUCTIONS

Golgi-impregnated pyramidal neurons were readily identified by their characteristic triangular somal shape, apical dendrite extending toward the pial surface, and numerous dendritic spines. The following criteria were used to select pyramidal neurons for reconstruction: (1) location of the cell soma in layer 3 and within the middle of the thickness (z-axis) of the section; (2) full impregnation of the neuron; (3) soma or dendrites not obscured by overlying opaque artifacts larger than 5 µm; (4) no morphologic changes attributable to PMI43; and (5) presence of at least 3 primary basilar dendritic shafts, each of which branched at least once. For each subject, 15 neurons were randomly sampled in each of 3 locations: (1) the superficial half of layer 3 (20%-37% of the total cortical depth) in area 46, (2) the deep half of layer 3 (38%-55% of the total cortical depth) in area 46, and (3) layer 3 of area 17. The adequacy of these sampling procedures for detecting differences in spine density has been previously demonstrated.32,39,44

For each neuron, the longest basilar dendrite, including all branches, was reconstructed in 3 dimensions with a tracing system (Neuron Tracing System; Eutectics Electronics Inc, Raleigh, NC) and a ×100 oil immersion objective (Figure 1). Only those portions of the dendritic tree within the same section as the cell soma were reconstructed. Because apical dendrites are frequently truncated during sectioning, these dendrites were not examined. Each dendritic branch was recorded as having either a natural end (gradual tapering of dendritic thickness with an end swelling, spine, or spine cluster) or an artificial end (cut dendrite).39 For each basilar dendrite and its branches, the mean diameter and total length, the location and number of spines, the total number of dendritic segments (the portion of a dendrite located between either the soma or a dendritic bifurcation and either another bifurcation or the dendrite end), and the maximum branch order (highest numbered dendritic segment) of the dendrites were determined. The cross-sectional area of each cell body was determined by tracing its outline. All neurons were reconstructed by the same investigator (L.A.G.) without knowledge of the subject number or diagnostic group.

Place holder to copy figure label and caption
Figure 1.

Reconstruction of a basilar dendrite from a layer 3 pyramidal neuron in control subject 516. Fourth-order dendritic branches are present. For each neuron, calculation of dendritic spine density included the total length of the dendrite shown. The bar indicates 50 µm.

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STATISTICAL ANALYSES

For each parameter measured, the results were analyzed using a multivariate analysis of covariance model with the independent variables of diagnostic group, sex, age, race, PMI, and tissue fixation time. The multiple observations per subject (15 neurons) for a particular parameter were treated as a multivariate observation. Because the measured parameters within a given subject were possibly correlated and were also exchangeable, they were modeled as repeated measures with a compound, symmetric covariance structure. To preserve degrees of freedom, the interactions with diagnostic group were only examined if the effect of a particular independent variable was significant (P<.05). For any neuron parameter in which the multivariate analysis of covariance test yielded a significant diagnostic group effect at the .05 level, post hoc simultaneous pairwise comparisons using the Bonferroni procedure at the .05 level were conducted to determine which of the groups' means differed significantly. Simultaneous 95% confidence intervals were also obtained for each pairwise comparison of diagnostic groups. Finally, paired t tests were used to compare spine density across layers within subject groups.

SPINE DENSITY ON LAYER 3 PYRAMIDAL NEURONS

The Golgi impregnation procedure clearly filled the basilar dendritic shafts and spines of layer 3 pyramidal neurons. As shown in Figure 2, differences in spine density among neurons and across brains were sometimes quite evident.

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Figure 2.

Brightfield photomicrographs illustrating Golgi-impregnated basilar dendrites and spines on dorsolateral prefrontal cortex layer 3 pyramidal neurons from normal control subject 390 (A) and 2 subjects with schizophrenia (subjects 410 [B] and 466 [C]). The calibration bar equals 10 µm.

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In DLPFC area 46 (Table 3), the mean spine density on the basilar dendrites of pyramidal neurons in superficial layer 3 of the schizophrenic subjects was 15% lower than that of the normal controls and 13% lower than that of the psychiatric subjects (Figure 3, A). However, these differences did not achieve statistical significance (F2,37 = 2.52, P = .09).

Table Graphic Jump LocationTable 3. Dendritic Parameters From Layer 3 Pyramidal Neurons in the DLPFC (Area 46)*
Place holder to copy figure label and caption
Figure 3.

Scatterplots illustrating mean spine densities for 15 pyramidal neurons per subject in the superficial (A) and deep (B) portions of layer 3 in dorsolateral prefrontal cortex area 46, and in area 17, primary visual cortex (C). Horizontal lines indicate group means; C, control subjects; S, schizophrenic subjects; and P, psychiatric subjects.

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In contrast, the spine density on the basilar dendrites of pyramidal neurons in deep layer 3 of area 46 did significantly differ (F2,37 = 6.01, P = .006) among the 3 subject groups (Table 3).There was also a main effect for age (F1,37 = 8.49, P = .006) on spine density, but reanalysis failed to reveal a significant age-by-diagnosis interaction (F2,36 = 1.87, P = .17). In addition, there was no effect of race, sex, PMI, or tissue fixation time (F1,37<0.86, P>.47) on spine density.

As shown in Figure 3, B, the mean spine density on pyramidal neurons in deep layer 3 was 23% lower (95% confidence interval, −42.3% to −6.7%) in the schizophrenic subjects than in the normal controls, a difference significant at P = .004 by post hoc comparisons. Furthermore, although spine density did not differ (t = 0.52, P = .61) between superficial and deep layer 3 pyramidal neurons in the normal controls (Table 3), spine density was significantly (t = 3.65, P = .003) decreased by 11% in deep layer 3 relative to superficial layer 3 in the subjects with schizophrenia. These comparisons confirm a laminar specificity to the spine density differences between schizophrenic and normal control subjects.

Compared with the psychiatric subjects, the mean spine density on deep layer 3 pyramidal neurons in the schizophrenic subjects was decreased by 16%. Although this difference did not achieve statistical significance (P = .08), the 95% confidence interval (−35.8% to 4.4%) was suggestive of a reduction in spine density in the schizophrenic subjects compared with the psychiatric subjects. In contrast, the mean spine density clearly did not differ (P = .81) between the psychiatric and control subjects.

In contrast to area 46, the spine density on layer 3 pyramidal neurons in area 17 (Figure 3, C), primary visual cortex, was decreased in the schizophrenic (13%) and psychiatric (11%) subjects relative to the normal controls (Table 4). However, these differences did not achieve statistical significance (F2,34 = 2.70, P = .08).

Table Graphic Jump LocationTable 4. Dendritic Parameters From Layer 3 Pyramidal Neurons in the Primary Visual Cortex (Area 17)*
OTHER PARAMETERS OF LAYER 3 PYRAMIDAL NEURONS

In superficial layer 3 of area 46, only somal size significantly (F2,37 = 3.84, P = .03) differed among the 3 groups, and post hoc comparisons revealed that this difference was due to a smaller somal size in the psychiatric subjects compared with the normal controls (Table 3). In deep layer 3 of area 46, only total dendritic length (TDL) differed significantly (F2,37 = 4.17, P = .02) among the 3 groups. Post hoc comparisons revealed that the normal control group had a significantly (P<.05) greater TDL than the schizophrenic and psychiatric groups, which did not differ from each other. Interestingly, an analysis of covariance for spine density, controlling for TDL, in the schizophrenic and control groups revealed that the group difference in spine density on deep layer 3 pyramidal neurons was more highly significant (F1,27 = 15.2, P<.001) than that indicated by the initial analysis. In layer 3 of the primary visual cortex, TDL (F2,34 = 4.11, P = .03), number of branch segments (F2,34 = 4.41, P = .02), and maximum branch order (F2,34 = 4.27, P = .02) differed significantly among the diagnostic groups (Table 4). For each measure, the main effect was due to significantly lower values in the psychiatric subjects compared with the control and schizophrenic subjects.

EFFECT OF ANTIPSYCHOTIC MEDICATIONS ON SPINE DENSITY

To determine whether treatment with antipsychotic medications might account for the decreased spine density on DLPFC deep layer 3 pyramidal neurons in the schizophrenic subjects, we conducted a separate analysis of the 9 psychiatric subjects who had been treated with these medications (Table 1). The mean (±SD) spine density (measured as number of spines per micrometer) on deep layer 3 pyramidal neurons in these subjects (0.30 ± 0.07) did not significantly differ from that of either the entire group of normal controls (0.33 ± 0.08, F1,18 = 0.47, P = .50) or a subset of 9 normal controls (0.31 ± 0.05, F1,12 = 0.06, P = .81) who, as a group, did not differ from the antipsychotic-treated psychiatric subjects in sex, age, or PMI.

These findings demonstrate that the density of basilar dendritic spines on deep layer 3 pyramidal neurons is significantly decreased in DLPFC area 46 of subjects with schizophrenia. This decrease does not appear to be a general correlate of having a psychiatric illness or a consequence of treatment with antipsychotic medications, suggesting that the decrease in spine density may be specific to the pathophysiological characteristics of schizophrenia. Because dendritic spine density directly reflects the number of excitatory inputs to pyramidal neurons,35,36 these findings, in concert with those of a pilot study45 that also reported decreased spine density on prefrontal layer 3 pyramidal neurons, support the hypothesis that schizophrenia is associated with diminished synaptic connectivity of the DLPFC.

In superficial layer 3 of area 46 and in layer 3 of area 17, pyramidal cells exhibited a trend toward decreased spine density in the schizophrenic subjects compared with the normal controls. Evidence suggestive of decreased cortical neuropil has been reported in both of these cortical regions.10 However, in area 17, the psychiatric subjects also showed a trend toward decreased spine density on layer 3 pyramidal neurons. In addition, other measures of dendritic morphologic characteristics (TDL, number of branch segments, and maximum branch order) appeared to be altered in area 17 of the psychiatric subjects, suggesting that a history of depression or death by suicide may be associated with altered neuronal morphologic characteristics in the primary visual cortex.

Interpretation of the pathophysiological significance of reduced spine density in the DLPFC requires a consideration of the potential influence of other factors. First, only a small percentage of neurons are labeled with the Golgi technique.46 However, because the impregnation process is random, the cells reconstructed in this study are likely to be representative of the neuronal populations of interest. This interpretation is supported by our finding of a 9% to 12% decrease in mean somal size of layer 3 pyramidal neurons in the DLPFC of the schizophrenic subjects. Although these differences were not significant, perhaps because of sample size, their magnitude is consistent with that of other reports47,48 that measured somal size in much larger samples of Nissl-stained neurons. Second, because the reaction product of the Golgi impregnation procedure is opaque, some spines are hidden behind the dendritic shaft and are not counted. Consequently, the spine densities reported in this study are relative and not absolute. However, previous studies49 have demonstrated that relative spine counts accurately reflect absolute numbers if comparisons are made between dendrites with similar shaft diameters, and, as shown in Table 3 and Table 4, mean dendritic diameter did not differ across our subject groups. Third, the schizophrenic and psychiatric subjects available for this study were somewhat diagnostically heterogeneous. However, the mean (±SD) spine density in DLPFC deep layer 3 of the subjects with "pure" schizophrenia (0.25 ± 0.06; n = 10) was 23% lower than that of the normal controls (0.32 ± 0.07; n = 14) and of the psychiatric subjects with major depression (0.33 ± 0.04; n = 10).

All of the schizophrenic subjects in this study had a history of treatment with antipsychotic agents. Studies addressing the effect of haloperidol on spine density in the rat prefrontal cortex have been inconclusive, with spine density reported to be decreased following high-dose, short-term treatment50 but unchanged following long-term treatment at levels more consistent with clinical practice.51 However, 3 lines of evidence suggest that antipsychotic medications do not account for the decreased dendritic spine density observed in the present study. First, the decrease in spine density exhibited regional and laminar specificity, an effect that is not readily explained by systemically administered agents. Second, the 4 schizophrenic subjects (subjects 410, 450, 537, and 622) who were not taking medications (for an average of 5.4 months) at the time of death actually had a lower spine density (0.24 ± 0.08) in deep layer 3 of area 46 than did the 11 subjects who were taking medications (0.26 ± 0.06). Finally, the 9 psychiatric subjects who had been treated with antipsychotic medications did not differ in spine density from normal controls. However, the lifetime exposure to antipsychotic medications is likely to have been lower in these psychiatric subjects than in the schizophrenic subjects.

Although decreased spine density represents a morphologic abnormality in the DLPFC of schizophrenic subjects, dendritic spines are relatively plastic structures. For example, spine number has been reported to change rapidly in certain brain regions of experimental animals under various conditions.5257 Although we cannot completely exclude the influence of such factors, their impact may have been minimized by the study design. For example, the comparison with subjects with mood or other psychotic disorders provides some assessment of the influence of environmental factors, such as hospitalizations, medications, and limitations in social and occupational activities, associated with being severely ill with a psychiatric disorder. In addition, spine density in deep layer 3 of area 46 was not associated with the duration of illness in either the schizophrenic (r = −0.358, P = .26) or psychiatric (r = −0.009, P = .98) subjects. However, the plasticity of dendritic spines suggests that the findings of this study, like many other observations in postmortem studies (alterations in gene expression or neurotransmitter receptor number), may not reflect a fixed lesion in the DLPFC of schizophrenic subjects.

Because the presynaptic and postsynaptic elements of axospinous synapses change in parallel,35,54,5860 the decreased spine density in schizophrenic subjects is likely to reflect a diminished number of excitatory synaptic inputs to DLPFC layer 3 pyramidal neurons. This interpretation is consistent with previous reports10,11,2325 of decreased synaptophysin protein and neuropil measures in the DLPFC of schizophrenic subjects. Interestingly, dendritic spine density on layer 3 pyramidal neurons undergoes a substantial decline during adolescence in primates.32 In addition, the density of asymmetric (presumably excitatory) synapses changes in a similar manner in the monkey and human DLPFC.33,34 These late developmental refinements in the excitatory circuitry of the DLPFC coincide with the age when the clinical manifestations of schizophrenia frequently first appear, suggesting that they may contribute to the pathophysiological characteristics of this disorder.61 However, we cannot determine from the present study whether the presynaptic terminals to DLPFC layer 3 pyramidal neurons never developed, were extensively pruned during adolescence, or were resorbed later in life.

The functional significance of a decrease in excitatory inputs depends on which population(s) of axon terminals is affected. Several lines of evidence suggest that the affected inputs may be from the mediodorsal thalamic nucleus. First, this nucleus has been reported to have fewer neurons in schizophrenic subjects.2931 Second, spine density was preferentially decreased on pyramidal neurons in deep layer 3 of the DLPFC. The basilar dendrites of these neurons typically extend through deep layer 3 and layer 4, the termination zone of afferents from the mediodorsal thalamic nucleus,27 and dendritic spines appear to be the principal synaptic targets of thalamic projections.28,62 Finally, decreased expression of the messenger RNA for GAD67, the synthesizing enzyme for γ-aminobutyric acid, in the DLPFC of schizophrenic subjects62,63 has been suggested to represent a compensatory response to diminished excitatory thalamic drive,64 since decreased activity in thalamic inputs to sensory cortices produces a down-regulation of GAD67 expression.65,66

However, the observations of this study may not be fully explained by a reduction in thalamic inputs to the DLPFC. For example, thalamocortical afferents appear to compose a small proportion (<10%) of the total excitatory inputs to the targeted cortical neurons in the cat visual cortex.67 If these findings can be extrapolated to the human DLPFC, then even a complete loss of thalamocortical afferents would not be sufficient to account for the observed 16% to 23% decrease in basilar dendritic spine density on deep layer 3 pyramidal cells in the schizophrenic subjects. Two other major sources of excitatory inputs to deep and superficial layer 3 DLPFC pyramidal neurons are intrinsic axon collaterals from other pyramidal neurons68,69 and associational or callosal projections from other cortical regions.6971 Thus, given the trend for spine density to also be decreased on superficial layer 3 pyramidal cells, it may be that abnormalities in thalamocortical afferents to deep layer 3 have an additive effect to a disturbance in cortical axon terminals that are distributed across layer 3. However, our findings do not reveal the direction of the pathophysiological changes. For example, it is possible that the inputs to DLPFC layer 3 pyramidal cells are reduced not because of a more primary disturbance in the source of the inputs but because an abnormality intrinsic to these pyramidal cells renders them unable to support a normal complement of excitatory inputs.

In summary, our findings provide evidence for a decrease in excitatory inputs to DLPFC layer 3 pyramidal cells that may be most marked for pyramidal cells located in the thalamic recipient zone. Given the role of thalamic excitatory inputs in the mediation of working memory,72,73 these findings may contribute to the pathophysiological basis for the disturbance of these cognitive abilities in subjects with schizophrenia.

Accepted for publication July 22, 1999.

This study was supported by grants MH00519 and MH45156 from the US Public Health Service, Bethesda, Md; and the Scottish Rite Schizophrenia Research Program, N.M.J., Lexington, Mass.

We thank Allan Sampson, PhD, and Sungyoung Auh, MA, for statistical consultations; and Mary Brady for photographic assistance.

Reprints: David A. Lewis, MD, University of Pittsburgh, 3811 O'Hara St, W1650 Biomedical Science Tower, Pittsburgh, PA 15213 (e-mail: lewisda@msx.upmc.edu).

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Perrone-Bizzozero  NISower  ACBird  EDBenowitz  LIIvins  KJNeve  RL Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc Natl Acad Sci U S A. 1996;9314182- 14187
Link to Article
Honer  WGFalkai  PChen  CArango  VMann  JJDwork  AJ Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience. 1999;911247- 1255
Link to Article
Giguere  MGoldman-Rakic  PS Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J Comp Neurol. 1988;277195- 213
Link to Article
Melchitzky  DSSesack  SRLewis  DA Parvalbumin-immunoreactive axon terminals in monkey and human prefrontal cortex: laminar, regional and target specificity of type I and type II synapses. J Comp Neurol. 1999;40811- 22
Link to Article
Pakkenberg  B Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry. 1990;471023- 1028
Link to Article
Manaye  KFLiang  C-LHicks  PBGerman  DYoung  KA Nerve cell numbers in thalamic anterior and mediodorsal nuclei are selectively reduced in schizophrenia. Soc Neurosci Abstracts. 1998;241236
Popken  GJBunney  WE  JrPotkin  SGJones  EG Neuron number and GABAergic and glutamatergic mRNA expression in subdivisions of the thalamic mediodorsal nucleus of schizophrenics. Soc Neurosci Abstracts. 1998;24991
Anderson  SAClassey  JDCondé  FLund  JSLewis  DA Synchronous development of pyramidal neuron dendritic spines and parvalbumin-immunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Neuroscience. 1995;677- 22
Link to Article
Bourgeois  J-PGoldman-Rakic  PSRakic  P Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;478- 96
Link to Article
Huttenlocher  PRDabholkar  AS Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol. 1997;387167- 178
Link to Article
DeFelipe  JFarinas  I The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog Neurobiol. 1992;39563- 607
Link to Article
Peters  APalay  SLWebster  DF The Fine Structure of the Nervous System.  New York, NY Oxford University Press1991;
Mirra  SSHeyman  AMcKeel  DSumi  SMCrain  BJBrownlee  LMVogel  FSHughes  JPvan Bell  G The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathological assessment of Alzheimer's disease. Neurology. 1991;41479- 486
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised.  Washington, DC American Psychiatric Association1987;
Hayes  TLLewis  DA Magnopyramidal neurons in the anterior motor speech region: dendritic features and interhemispheric comparisons. Arch Neurol. 1996;531277- 1283
Link to Article
Lund  JS Organization of neurons in the visual cortex, area 17, of the monkey (Macaca mulatta). J Comp Neurol. 1973;147455- 496
Link to Article
Lewis  DACampbell  MJTerry  RDMorrison  JH Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices. J Neurosci. 1987;71799- 1808
Woo  T-UWhitehead  REMelchitzky  DSLewis  DA A subclass of prefrontal γ-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci U S A. 1998;955341- 5346
Link to Article
Williams  RSFerrante  RJCaviness  VS  Jr The Golgi rapid method in clinical neuropathology: the morphologic consequences of suboptimal fixation. J Neuropathol Exp Neurol. 1978;3713- 33
Link to Article
Jacobs  BDriscoll  LSchall  M Life-span dendritic and spine changes in areas 10 and 18 of human cortex: a quantitative Golgi study. J Comp Neurol. 1997;386661- 680
Link to Article
Garey  LJOng  WYPatel  TSKanani  MDavis  AMortimer  AMBarnes  TREHirsch  SR Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry. 1998;65446- 453
Link to Article
Pasternak  JFWoolsey  TA On the selectivity of the Golgi-Cox method. J Comp Neurol. 1975;160307- 312
Link to Article
Pierri  JNEdgar  CLLewis  DA Somal size of prefrontal cortical pyramidal neurons in the thalamic recipient zone of subjects with schizophrenia. Soc Neurosci Abstracts. 1998;24987
Rajkowska  GSelemon  LDGoldman-Rakic  PS Neuronal and glial somal size in the prefrontal cortex. Arch Gen Psychiatry. 1998;55215- 224
Link to Article
Horner  CHArbuthnott  E Methods of estimation of spine density: are spines evenly distributed throughout the dendritic field? J Anat. 1991;177179- 184
Benes  FMPaskevich  PADavidson  JDomesick  VB Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats. Brain Res. 1985;34815- 20
Link to Article
Vincent  SLMcSparren  JWang  RYBenes  FM Evidence for ultrastructural changes in cortical axodendritic synapses following long-term treatment with haloperidol or clozapine. Neuropsychopharmacology. 1991;5147- 155
Brock  JWPrasad  C Alterations in dendritic spine density in the rat brain associated with protein malnutrition. Dev Brain Res. 1992;66266- 269
Link to Article
Bryan  GKRiesen  AH Deprived somatosensory-motor experience in stumptailed monkey neocortex: dendritic spine density and dendritic branching of layer IIIb pyramidal cells. J Comp Neurol. 1989;286208- 217
Link to Article
Horner  CH Plasticity of the dendritic spine. Prog Neurobiol. 1993;41281- 321
Link to Article
Valverde  F Apical dendritic spines of the visual cortex and light deprivation in the mouse. Exp Brain Res. 1967;3337- 352
Link to Article
Woolley  CSGould  EFrankfurt  MMcEwen  BS Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci. 1990;104035- 4039
Moser  M-BTrommald  MAndersen  P An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc Natl Acad Sci U S A. 1994;9112673- 12675
Link to Article
Parnavelas  JGLynch  GBrecha  NCotman  CWGlobus  A Spine loss and regrowth in hippocampus following deafferentation. Nature. 1974;24871- 73
Link to Article
Ingham  CAHood  SHTaggart  PArbuthnott  GW Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway. J Neurosci. 1998;184732- 4743
Globus  AScheibel  AB Synaptic loci on parietal cortical neurons: terminations of corpus callosum fibers. Science. 1967;1561127- 1129
Link to Article
Lewis  DA Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology. 1997;16385- 398
Link to Article
Kuroda  MMurakami  KShinkai  MOjima  HKishi  K Electron microscopic evidence that axon terminals from the mediodorsal thalamic nucleus make direct synaptic contacts with callosal cells in the prelimbic cortex of the rat. Brain Res. 1995;677348- 353
Link to Article
Volk  DWAustin  MCLewis  DA Decreased expression of GAD67 mRNA in a subpopulation of GABA neurons in the prefrontal cortex of schizophrenic subjects. Soc Neurosci Abstracts. 1998;24986
Lewis  DA Neural circuitry of the prefrontal cortex in schizophrenia. Arch Gen Psychiatry. 1995;52269- 273
Link to Article
Jones  EG GABAergic neurons and their role in cortical plasticity in primates. Cereb Cortex. 1993;3361- 372
Link to Article
Benson  DLHuntsman  MMJones  EG Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys. Cereb Cortex. 1994;440- 51
Link to Article
Ahmed  BAnderson  JCDouglas  RJMartin  KACNelson  JC Polyneuronal innervation of spiny stellate neurons in cat visual cortex. J Comp Neurol. 1994;34139- 49
Link to Article
Levitt  JBLewis  DAYoshioka  TLund  JS Topography of pyramidal neuron intrinsic connections in macaque monkey prefrontal cortex (areas 9 and 46). J Comp Neurol. 1993;338360- 376
Link to Article
Pucak  MLLevitt  JBLund  JSLewis  DA Patterns of intrinsic and associational circuitry in monkey prefrontal cortex. J Comp Neurol. 1996;376614- 630
Link to Article
Barbas  H Architecture and cortical connections of the prefrontal cortex in the rhesus monkey. Adv Neurol. 1992;5791- 115
Goldman-Rakic  PSSchwartz  ML Interdigitation of contralateral and ipsilateral columnar projections to frontal association cortex in primates. Science. 1982;216755- 757
Link to Article
Goldman-Rakic  PS Cellular basis of working memory. Neuron. 1995;14477- 485
Link to Article
Lewis  DAAnderson  SA The functional architecture of the prefrontal cortex and schizophrenia. Psychol Med. 1995;25887- 894
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Reconstruction of a basilar dendrite from a layer 3 pyramidal neuron in control subject 516. Fourth-order dendritic branches are present. For each neuron, calculation of dendritic spine density included the total length of the dendrite shown. The bar indicates 50 µm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Brightfield photomicrographs illustrating Golgi-impregnated basilar dendrites and spines on dorsolateral prefrontal cortex layer 3 pyramidal neurons from normal control subject 390 (A) and 2 subjects with schizophrenia (subjects 410 [B] and 466 [C]). The calibration bar equals 10 µm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Scatterplots illustrating mean spine densities for 15 pyramidal neurons per subject in the superficial (A) and deep (B) portions of layer 3 in dorsolateral prefrontal cortex area 46, and in area 17, primary visual cortex (C). Horizontal lines indicate group means; C, control subjects; S, schizophrenic subjects; and P, psychiatric subjects.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Characteristics of Control, Schizophrenic, and Psychiatric Subjectsa
Table Graphic Jump LocationTable 2. Summary of Subject Characteristics*
Table Graphic Jump LocationTable 3. Dendritic Parameters From Layer 3 Pyramidal Neurons in the DLPFC (Area 46)*
Table Graphic Jump LocationTable 4. Dendritic Parameters From Layer 3 Pyramidal Neurons in the Primary Visual Cortex (Area 17)*

References

Park  SHolzman  PS Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry. 1992;49975- 982
Link to Article
Weinberger  DRBerman  KFZec  RF Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry. 1986;43114- 124
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Steinberg  JLDevous  MDPaulman  RG Wisconsin card sorting activated regional cerebral blood flow in first break and chronic schizophrenic patients and normal controls. Schizophr Res. 1996;19177- 187
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Andreasen  NCFlashman  LFlaum  MArndt  SSwayze  V  IIO'Leary  DSEhrhardt  JCYuh  WTC Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging. JAMA. 1994;2721763- 1769
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Schlaepfer  TEHarris  GJTien  AYPeng  LWLee  SFederman  EBChase  GABarta  PEPearlson  GD Decreased regional cortical gray matter volume in schizophrenia. Am J Psychiatry. 1994;151842- 848
Shelton  RCKarson  CNDoran  ARPickar  DBigelow  LBWeinberger  DR Cerebral structural pathology in schizophrenia: evidence for a selective prefrontal cortical defect. Am J Psychiatry. 1988;145154- 163
Sullivan  EVLim  KOMathalon  DMarsh  LBeal  DMHarris  DHoff  ALFaustman  WOPfefferbaum  A A profile of cortical gray matter volume deficits characteristic of schizophrenia. Cereb Cortex. 1998;8117- 124
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Zipursky  RBLim  KOSullivan  EVBrown  BWPfefferbaum  A Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49195- 205
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Daviss  SRLewis  DA Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons. Psychiatry Res. 1995;5981- 96
Link to Article
Selemon  LDRajkowska  GGoldman-Rakic  PS Abnormally high neuronal density in the schizophrenic cortex: a morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry. 1995;52805- 818
Link to Article
Selemon  LDRajkowska  GGoldman-Rakic  PS Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method. J Comp Neurol. 1998;392402- 412
Link to Article
Akbarian  SKim  JJPotkin  SGHagman  JOTafazzoli  ABunney  WE  JrJones  EG Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry. 1995;52258- 266
Link to Article
Thune  JJHofsten  DEUylings  HBMPakkenberg  B Total neuron numbers in the prefrontal cortex in schizophrenia. Soc Neurosci Abstracts. 1998;24985
Goldman-Rakic  PSSelemon  LD Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull. 1997;23437- 458
Link to Article
Bertolino  ANawroz  SMattay  VSBarnett  ASDuyn  JHMoonen  CTWFrank  JATedeschi  GWeinberger  DR Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry. 1996;1531554- 1563
Bertolino  ACallicott  JHNawroz  SMattay  VSDuyn  JHTecleschi  GFrank  JAWeinberger  DR Reproducibility of proton magnetic resonance spectroscopic imaging in patients with schizophrenia. Neuropsychopharmacology. 1998;181- 9
Link to Article
Buckley  PFMoore  CLong  HLarkin  CThompson  PMulvany  FRedmond  OStack  JPEnnis  JTWaddington  JL 1H-magnetic resonance spectroscopy of the left temporal and frontal lobes in schizophrenia: clinical, neurodevelopmental, and cognitive correlates. Biol Psychiatry. 1994;36792- 800
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Deicken  RFZhou  LCorwin  FVinogradov  SWeiner  MW Decreased left frontal lobe N-acetylaspartate in schizophrenia. Am J Psychiatry. 1997;154688- 690
Pettegrew  JWKeshavan  MSPanchalingam  KStrychor  SKaplan  DBTretta  MGAllen  M Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. Arch Gen Psychiatry. 1991;48563- 568
Link to Article
Shioiri  TKato  TInubushi  TMurashita  JTakahashi  S Correlations of phosphomonoesters measured by phosphorus-31 magnetic resonance spectroscopy in the frontal lobes and negative symptoms in schizophrenia. Psychiatr Res Neuroimaging. 1994;55223- 235
Link to Article
Stanley  JAWilliamson  PCDrost  DJCarr  TJRylett  RJMalla  AThompson  RT An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy. Arch Gen Psychiatry. 1995;52399- 406
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Pettegrew  JWKeshavan  MSMinshew  NJ 31P nuclear magnetic resonance spectroscopy: neurodevelopment and schizophrenia. Schizophr Bull. 1993;1935- 53
Link to Article
Glantz  LALewis  DA Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia: regional and diagnostic specificity. Arch Gen Psychiatry. 1997;54943- 952
Link to Article
Karson  CNMrak  RESchluterman  KOSturner  WQSheng  JGGriffin  WST Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for "hypofrontality." Mol Psychiatry. 1999;439- 45
Link to Article
Perrone-Bizzozero  NISower  ACBird  EDBenowitz  LIIvins  KJNeve  RL Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc Natl Acad Sci U S A. 1996;9314182- 14187
Link to Article
Honer  WGFalkai  PChen  CArango  VMann  JJDwork  AJ Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience. 1999;911247- 1255
Link to Article
Giguere  MGoldman-Rakic  PS Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J Comp Neurol. 1988;277195- 213
Link to Article
Melchitzky  DSSesack  SRLewis  DA Parvalbumin-immunoreactive axon terminals in monkey and human prefrontal cortex: laminar, regional and target specificity of type I and type II synapses. J Comp Neurol. 1999;40811- 22
Link to Article
Pakkenberg  B Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry. 1990;471023- 1028
Link to Article
Manaye  KFLiang  C-LHicks  PBGerman  DYoung  KA Nerve cell numbers in thalamic anterior and mediodorsal nuclei are selectively reduced in schizophrenia. Soc Neurosci Abstracts. 1998;241236
Popken  GJBunney  WE  JrPotkin  SGJones  EG Neuron number and GABAergic and glutamatergic mRNA expression in subdivisions of the thalamic mediodorsal nucleus of schizophrenics. Soc Neurosci Abstracts. 1998;24991
Anderson  SAClassey  JDCondé  FLund  JSLewis  DA Synchronous development of pyramidal neuron dendritic spines and parvalbumin-immunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Neuroscience. 1995;677- 22
Link to Article
Bourgeois  J-PGoldman-Rakic  PSRakic  P Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;478- 96
Link to Article
Huttenlocher  PRDabholkar  AS Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol. 1997;387167- 178
Link to Article
DeFelipe  JFarinas  I The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog Neurobiol. 1992;39563- 607
Link to Article
Peters  APalay  SLWebster  DF The Fine Structure of the Nervous System.  New York, NY Oxford University Press1991;
Mirra  SSHeyman  AMcKeel  DSumi  SMCrain  BJBrownlee  LMVogel  FSHughes  JPvan Bell  G The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathological assessment of Alzheimer's disease. Neurology. 1991;41479- 486
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised.  Washington, DC American Psychiatric Association1987;
Hayes  TLLewis  DA Magnopyramidal neurons in the anterior motor speech region: dendritic features and interhemispheric comparisons. Arch Neurol. 1996;531277- 1283
Link to Article
Lund  JS Organization of neurons in the visual cortex, area 17, of the monkey (Macaca mulatta). J Comp Neurol. 1973;147455- 496
Link to Article
Lewis  DACampbell  MJTerry  RDMorrison  JH Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices. J Neurosci. 1987;71799- 1808
Woo  T-UWhitehead  REMelchitzky  DSLewis  DA A subclass of prefrontal γ-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc Natl Acad Sci U S A. 1998;955341- 5346
Link to Article
Williams  RSFerrante  RJCaviness  VS  Jr The Golgi rapid method in clinical neuropathology: the morphologic consequences of suboptimal fixation. J Neuropathol Exp Neurol. 1978;3713- 33
Link to Article
Jacobs  BDriscoll  LSchall  M Life-span dendritic and spine changes in areas 10 and 18 of human cortex: a quantitative Golgi study. J Comp Neurol. 1997;386661- 680
Link to Article
Garey  LJOng  WYPatel  TSKanani  MDavis  AMortimer  AMBarnes  TREHirsch  SR Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry. 1998;65446- 453
Link to Article
Pasternak  JFWoolsey  TA On the selectivity of the Golgi-Cox method. J Comp Neurol. 1975;160307- 312
Link to Article
Pierri  JNEdgar  CLLewis  DA Somal size of prefrontal cortical pyramidal neurons in the thalamic recipient zone of subjects with schizophrenia. Soc Neurosci Abstracts. 1998;24987
Rajkowska  GSelemon  LDGoldman-Rakic  PS Neuronal and glial somal size in the prefrontal cortex. Arch Gen Psychiatry. 1998;55215- 224
Link to Article
Horner  CHArbuthnott  E Methods of estimation of spine density: are spines evenly distributed throughout the dendritic field? J Anat. 1991;177179- 184
Benes  FMPaskevich  PADavidson  JDomesick  VB Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats. Brain Res. 1985;34815- 20
Link to Article
Vincent  SLMcSparren  JWang  RYBenes  FM Evidence for ultrastructural changes in cortical axodendritic synapses following long-term treatment with haloperidol or clozapine. Neuropsychopharmacology. 1991;5147- 155
Brock  JWPrasad  C Alterations in dendritic spine density in the rat brain associated with protein malnutrition. Dev Brain Res. 1992;66266- 269
Link to Article
Bryan  GKRiesen  AH Deprived somatosensory-motor experience in stumptailed monkey neocortex: dendritic spine density and dendritic branching of layer IIIb pyramidal cells. J Comp Neurol. 1989;286208- 217
Link to Article
Horner  CH Plasticity of the dendritic spine. Prog Neurobiol. 1993;41281- 321
Link to Article
Valverde  F Apical dendritic spines of the visual cortex and light deprivation in the mouse. Exp Brain Res. 1967;3337- 352
Link to Article
Woolley  CSGould  EFrankfurt  MMcEwen  BS Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci. 1990;104035- 4039
Moser  M-BTrommald  MAndersen  P An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc Natl Acad Sci U S A. 1994;9112673- 12675
Link to Article
Parnavelas  JGLynch  GBrecha  NCotman  CWGlobus  A Spine loss and regrowth in hippocampus following deafferentation. Nature. 1974;24871- 73
Link to Article
Ingham  CAHood  SHTaggart  PArbuthnott  GW Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway. J Neurosci. 1998;184732- 4743
Globus  AScheibel  AB Synaptic loci on parietal cortical neurons: terminations of corpus callosum fibers. Science. 1967;1561127- 1129
Link to Article
Lewis  DA Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology. 1997;16385- 398
Link to Article
Kuroda  MMurakami  KShinkai  MOjima  HKishi  K Electron microscopic evidence that axon terminals from the mediodorsal thalamic nucleus make direct synaptic contacts with callosal cells in the prelimbic cortex of the rat. Brain Res. 1995;677348- 353
Link to Article
Volk  DWAustin  MCLewis  DA Decreased expression of GAD67 mRNA in a subpopulation of GABA neurons in the prefrontal cortex of schizophrenic subjects. Soc Neurosci Abstracts. 1998;24986
Lewis  DA Neural circuitry of the prefrontal cortex in schizophrenia. Arch Gen Psychiatry. 1995;52269- 273
Link to Article
Jones  EG GABAergic neurons and their role in cortical plasticity in primates. Cereb Cortex. 1993;3361- 372
Link to Article
Benson  DLHuntsman  MMJones  EG Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys. Cereb Cortex. 1994;440- 51
Link to Article
Ahmed  BAnderson  JCDouglas  RJMartin  KACNelson  JC Polyneuronal innervation of spiny stellate neurons in cat visual cortex. J Comp Neurol. 1994;34139- 49
Link to Article
Levitt  JBLewis  DAYoshioka  TLund  JS Topography of pyramidal neuron intrinsic connections in macaque monkey prefrontal cortex (areas 9 and 46). J Comp Neurol. 1993;338360- 376
Link to Article
Pucak  MLLevitt  JBLund  JSLewis  DA Patterns of intrinsic and associational circuitry in monkey prefrontal cortex. J Comp Neurol. 1996;376614- 630
Link to Article
Barbas  H Architecture and cortical connections of the prefrontal cortex in the rhesus monkey. Adv Neurol. 1992;5791- 115
Goldman-Rakic  PSSchwartz  ML Interdigitation of contralateral and ipsilateral columnar projections to frontal association cortex in primates. Science. 1982;216755- 757
Link to Article
Goldman-Rakic  PS Cellular basis of working memory. Neuron. 1995;14477- 485
Link to Article
Lewis  DAAnderson  SA The functional architecture of the prefrontal cortex and schizophrenia. Psychol Med. 1995;25887- 894
Link to Article

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