Postmortem studies of the subiculum from subjects with schizophrenia have detected smaller pyramidal cell bodies and diminished immunoreactivity for the dendritic protein, microtubule-associated protein 2. While these findings suggest that subicular pyramidal cell dendrites may be structurally altered in subjects with schizophrenia, this possibility had not been tested directly.
Rapid Golgi impregnation of archival brain specimens was used to compare the morphologic characteristics of subicular dendrites in subjects with schizophrenia (n=13) and mood disorders (n=6) with subjects without psychiatric disease (n=8). The specimens were processed and analyzed by physicians blind to diagnosis. The extent of dendritic trees in the subiculum and fusiform gyrus was examined by Sholl analysis. Spine density on apical dendrites of subicular pyramidal cells was determined at a fixed distance from the cell body.
Spine density and arborization of subicular apical dendrites were significantly related to diagnostic group. Spine density was significantly lower in the schizophrenia and mood disorder groups than in the nonpsychiatric group. Among the mood disorder cases, diminished spine density was apparently related to a strong family history of major psychiatric diseases. There were no significant effects of diagnostic group on Sholl analysis of nonapical subicular dendrites nor on Sholl analysis of dendrites of neocortical pyramidal cells in the fusiform gyrus.
We have observed an association between schizophrenia and major mood disorders and structural abnormalities of subicular apical dendrites. Further studies are needed to test this association in a larger sample and to evaluate the potential role of family history and of confounding factors, such as medications and chronic institutionalization.
ACONVERGENCE of functional and structural evidence presents elements of cerebral synapses as possible sites of a neuropathological lesion in subjects with schizophrenia. Goldman-Rakic and Selemon,1 citing evidence for decreased cortical volume but normal neuronal number in subjects with schizophrenia,2 state, "Our view is that certain neurons are dystrophic and undergo atrophy of their neuronal processes . . .".1(p442) Olney and Farber3 cite evidence for diminished N-methyl D-aspartate receptor–mediated transmission as a crucial factor in subjects with schizophrenia. Feinberg4 and Keshevan et al5 suggest excessive synaptic pruning as a possible cause of schizophrenia. Each of these hypotheses suggests a loss or alteration of synaptic targets. In the brain, axonal processes may form synapses on neuronal cell bodies, on other axons, or, in most cases, on dendrites. Dendritic synapses may be either on the shaft of the dendrite or on spinous processes that project from these shafts. More than 90% of all excitatory synapses in the central nervous system are on dendritic spines, and the structure of dendritic spines dictates their conductive properties. Thus, loss or alteration of spines would be expected to lead to abnormalities of glutamate transmission, even if presynaptic elements and postsynaptic receptors were maintained.6 Conversely, excitatory neurotransmission influences the size and shape of dendritic spines.
Indication for the study of structural abnormalities of dendrites also comes from reports of quantitative abnormalities in presynaptic proteins, which suggest possible alteration in the number or structure of synapses (eg, findings from the article by Young et al7). Such alterations would most likely be reflected in changes in both axon terminals and the dendrites on which they most commonly form synapses. Smaller cell bodies of subicular and hippocampal pyramidal cells8,9 may reflect diminished support of neuronal processes. Diminished immunoreactivity in subjects with schizophrenia for microtubule-associated protein 2 (MAP2),10,11 an important determinant of dendritic structure and plasticity, further suggests the possibility of structural abnormalities of dendrites, either as a cause or an effect of alterations in MAP2. This loss of MAP2 immunoreactivity is localized to the entorhinal cortex and subiculum, which relay inputs and outputs, respectively, between the adjacent hippocampus and various neocortical regions. Impaired subicular function could thus produce a disturbed relationship between emotion and thought, a fundamental feature of schizophrenia.12
Golgi impregnation permits examination of dendritic structure at the light microscopic level. The few Golgi studies in subjects with schizophrenia report loss of spines in neocortical pyramidal cells13,14 and dendritic abnormalities in the orbitofrontal cortex15 and brainstem reticular formation.16 Studies using electron microscopy demonstrate smaller spines17 and altered distribution of spines18 in the striatum. No Golgi or electron microscopic study has examined dendrites in the subiculum. We therefore compared this region in autopsy tissue from individuals who had been institutionalized for schizophrenia or mood disorders with a third group of individuals who had not experienced psychiatric disease.
Subjects, materials, and methods
All psychiatric subjects were long-term inpatients in state psychiatric hospitals; one young patient had been discharged at the time of death. Each subject's brain had been sent to our institution for routine neuropathological evaluation. Autopsies were performed at 4 psychiatric hospitals and 1 medical examiner's office. Six (46%) of the schizophrenia cases and 5 (83%) of the mood disorder cases were obtained from a single institution. The nonpsychiatric cases all were obtained from routine autopsies at Columbia-Presbyterian Medical Center, New York, NY. Cases were selected for similar age and postmortem interval in the 3 groups and for absence of Alzheimer disease or focal lesions in the hippocampal formation. Details are given in Table 1. Informed consent was obtained for all autopsies either from the next of kin or, in the absence of family, by the medical director of the institution in which the patient resided.
Clinical diagnoses were established by review of hospital records by a team of psychiatrists and psychologists blind to the autopsy results (J. K.). Diagnostic evaluations employed the modified Diagnostic Evaluation After Death, a medical record review protocol that has shown high interrater reliability (κ=0.643).19 All cases were reviewed by at least 2 raters. The reviews were discussed by the entire clinical diagnostic team, and consensus diagnoses were determined.20 The schizophrenia group included those subjects with a primary consensus diagnosis of schizophrenia (n=11) or schizoaffective disorder (n=2). The mood disorder group comprised 4 subjects with bipolar disorder, 1 with major depression, and 1 with depressive disorder not otherwise specified. The nonpsychiatric subjects were reviewed in the same manner as the psychiatric subjects and were included in the nonpsychiatric group only if there was no psychiatric diagnosis (n=7) or if the only psychiatric diagnosis was an adjustment disorder (n=1). Slightly fewer than half of the adult autopsy subjects at Columbia-Presbyterian Medical Center meet this criterion.
Subjects' family histories were derived from notes in the subjects' medical records and recorded in the modified Diagnostic Evaluation After Death by each rater. While all psychiatric records contained data on family history, these were not sufficiently detailed to allow rigorous application of DSM-IV criteria. No psychiatric illnesses were reported in the family histories of any of the subjects in the nonpsychiatric group.
Detailed neuropathological examinations were performed on all cases, as described previously.20 These included 2 diagnostic neuropathological reviews (with and without knowledge of demographic factors and clinical history) and an assessment of neuritic plaque and neurofibrillary tangle counts performed blind to all clinical and other neuropathological information.
The protocol for rapid Golgi impregnation (Leisa Glantz, PhD, e-mail communication, December 18, 1995) was modified from that previously described by Lund.21 From brains that had been fixed in formalin for 4.2 to 12.5 years, a 4-mm thick coronal block of the left hippocampus and subiculum (at the level of the lateral geniculate body) was impregnated in succession (over 18 days) with potassium dichromate and osmium tetroxide, graded solutions of silver nitrate, and collodion. Sections were cut at 90 µm. In most cases (11 of 13 in the schizophrenia group, 5 of 6 in the mood disorder group, and 6 of 8 in the nonpsychiatric group), the block extended sufficiently far laterally to include a portion of the fusiform gyrus (Figure 1).
Specimens from the 3 diagnostic groups were processed simultaneously, without knowledge of the clinical diagnosis. The cases were coded and reviewed in a random order, blind to diagnosis. Blindness was maintained throughout analysis.
From the subiculum of each subject (restricted to the area of the subiculum where the Golgi stain clearly allowed the distinction of external and internal pyramidal cell layers), and from the neocortex in those blocks that extended to the fusiform gyrus, the cell bodies and dendrites of the 5 best-impregnated internal pyramidal cells (or in neocortex layer V pyramidal neurons) were traced in 3 dimensions at magnification ×200 on a microscope (Leitz, Stuttgart, Germany) with a motorized stage (Ludl Electronic Products, Hawthorne, NY) and a computer display projected into the viewing field of the microscope (Lucivid; MicroBrightField, Colchester, Vt). Tracing employed the program Neurolucida (MicroBrightField). Dendritic tracings were quantified by Sholl23 analysis, performed by the Neurolucida software. This procedure constructs a series of equally spaced, spherical shells around the center of the cell body and then determines the number of dendritic processes intersecting each successive shell (ie, at each radius). Apical and basilar dendrites are treated separately. For analysis, each case was represented by the average value at a given shell radius for apical or basilar dendrites of all traced neurons in a given anatomical region (ie, subiculum or fusiform gyrus).
Spines were counted on the main shaft of the apical dendrite of 5 neurons in the internal pyramidal layer of the subiculum. Counts were made manually at magnification ×600 between 50 µm, and 100 µm from the cell body, as measured with a calibrated eyepiece graticule.
Data from Sholl analyses were analyzed by 2-tailed permutation test24 with the log likelihood ratio25 from mixed-model analysis26 as the test statistic. Four such analyses were performed, since each region (subiculum and fusiform gyrus) and each type of dendrite (apical and nonapical) was considered separately. When the result was statistically significant (α=.05), the analysis was repeated with each pair of groups, and the P values were multiplied by 3 to correct for multiple comparisons. Spine densities were compared by 2-tailed Kruskal-Wallis and Mann-Whitney tests.
Sholl analysis of dendritic trees
As measured by Sholl analysis (Figure 2), apical dendritic trees of subicular internal pyramidal cells were less extensive in the schizophrenia and mood disorder groups than in the nonpsychiatric group (permutation test, P=.04), while there were differences among groups neither for basilar dendrites of these cells (P=.45) nor for apical (P=.37) or basilar (P=.36) dendrites of neocortical pyramidal cells. Pairwise analysis of subicular apical values, corrected for 3 comparisons, yielded a significant difference (P=.06) between the schizophrenia and nonpsychiatric groups but not between the mood disorder and nonpsychiatric groups (P=.25) or the mood disorder and schizophrenia groups (P>.99).
The density of spines on apical dendrites of subicular internal pyramidal cells was markedly reduced in subjects with schizophrenia. This was readily apparent on inspection (Figure 3). There was a significant effect of diagnosis on spine density (Kruskal-Wallis χ22=14.3, P<.001), with significant differences between nonpsychiatric subjects and subjects with schizophrenia (U=0, W=78, P<.001, corrected for 3 comparisons) or subjects with mood disorder (P=.04) but not between subjects with mood disorder and schizophrenia (P>.99). There was no overlap between schizophrenia cases and nonpsychiatric cases, but the mood disorder cases were distributed bimodally, overlapping both groups (Figure 4).
Among the 6 subjects with mood disorder, 3 had spine densities similar to the nonpsychiatric cases, while 3 had spine densities similar to those of the subjects with schizophrenia. Although these numbers are too small to allow statistically meaningful observations, we reviewed the case histories carefully for distinguishing characteristics. The 2 groups did not differ in terms of age, sex, disease duration or severity, bipolarity, psychotic features, or treatment history. However, all 3 subjects with low spine density had at least 2 first-degree relatives with definite or probable mood disorders or schizophrenia (10 affected first-degree relatives, 9 of whom were treated in state psychiatric hospitals), while the 3 subjects with higher spine densities had no such relatives. Among the subjects with schizophrenia, there was no relationship between family history and dendritic spine density. The 2 subjects with schizoaffective disorder were typical of the schizophrenia group.
Potentially confounding factors
The 3 groups were similar regarding age, postmortem interval, and fixation interval, and within the range encountered in this study, there was no correlation between these factors and spine density or Sholl analysis. (For subicular apical dendritic intersections at a radius of 140 µm vs postmortem interval, r26=−0.15, P=.45 vs fixation interval, r26=−0.04, P=.85. For spine density vs postmortem interval, r25=−0.23, P=.26 vs fixation interval, r25=−0.07, P=.73. Similar results are obtained if diagnostic groups are analyzed individually.) No differences between men and women were apparent in any group.
All of the subjects in psychiatric groups had been treated with neuroleptic drugs. There was no apparent relationship between neuronal dendritic structure and the use of neuroleptic drugs within 1 year of death. Other somatic treatments were also common (Table 1); all of the subjects with mood disorder and all but one of the subjects with schizophrenia had received at least 1 of these treatments and most had received several. No treatment was associated with significant differences, within the schizophrenia group alone or within both psychiatric groups combined, in spine density or dendritic trees.
Structural abnormalities of subicular dendrites were found in a group of institutionalized subjects with schizophrenia and mood disorders. This finding is consistent with current theories regarding synaptic dysfunction in subjects with schizophrenia1-7 and could be either the cause or the result of such dysfunction. If the loss of apical dendritic spines is primary, postsynaptic proteins determining the size and shape of dendritic spines would be promising candidates for future biochemical and genetic studies.
The major inputs to the subiculum are from the CA1 field of the hippocampus via the alveus and from the entorhinal and adjacent transitional cortical areas via the perforant pathway. The positions of the afferent fibers are such that those from the hippocampus are more likely to synapse on the basilar dendrites of subicular pyramidal cells,27 while those from the entorhinal cortex are more likely to synapse with the apical dendrites of these cells.28 Other inputs to subicular apical dendrites are probably provided by subicular interneurons, dopaminergic projections from ventral tegmental area and medial pars compacta of the substantia nigra,29 and cholinergic projections from the amygdala,30 although these last 2 vary considerably within the mediolateral extent of the subiculum and the adjacent prosubiculum and presubiculum. The hippocampus contributes some fibers directly to the fornix, but most hippocampal output is relayed through the subiculum. Thus, while ablation of the subiculum, or a lesion involving the basilar dendrites or axons of its pyramidal cells, might be expected to interrupt this pathway and produce an amnestic syndrome, a lesion primarily involving apical dendrites would be more likely to affect the modulation of this output31 and to give rise to less predictable functional consequences.
We performed spine counts only on the apical dendrites of subicular internal pyramidal cells. Others have reported decreased numbers of spines on dendrites (apical and basilar combined) of pyramidal cells in the prefrontal cortex13 and temporal pole13 and on the basilar dendrites of pyramidal cells in the prefrontal cortex14 but not in the primary visual cortex.14 Although the differences in these areas are not so large as in the subiculum, further study is needed to determine the degree to which this abnormality is localized.
We found considerable morphological overlap between institutionalized subjects with schizophrenia and those with mood disorders. Regarding loss of spines, there was no overlap between the subjects with schizophrenia and control subjects. However, the values for the 6 subjects with mood disorder were split between 3 subjects whose values overlapped with those for the nonpsychiatric subjects and 3 whose values fell within the lower half of the values for the subjects with schizophrenia. Each of the 3 subjects with mood disorder with low spine density had at least 2 first-degree relatives with definite or probable schizophrenia or major mood disorder, while there were no such relatives among the 3 subjects with mood disorder with higher spine densities. The results must be interpreted with caution since the number of cases is small and the collection of family history was limited to review of the probands' medical records, a known pitfall.32 However, the findings suggest an overall similarity between schizophrenia and familial mood disorders.
Other recent studies found structural abnormalities of the hippocampal formation that may be similar in subjects with schizophrenia and subjects with mood disorders. One magnetic resonance imaging study revealed diminished left hippocampal volume in both first-episode schizophrenia and first-episode affective psychosis33 (although another magnetic resonance imaging study34 of first-episode cases found the reduction only in subjects with schizophrenia). Markedly reduced numbers of nonpyramidal cells in the CA2 field of the hippocampus were found in both subjects with schizophrenia and bipolar disorder,35 again raising long-standing questions about whether schizophrenia and mood disorders are distinct entities.36
Reduced volume37 and glial cell number38 have been reported in the subgenual prefrontal cortex of subjects with familial mood disorders, while absent in subjects with nonfamilial mood disorders. In these studies, subjects with familial mood disorder had relatives with mood disorders; data regarding relatives with schizophrenia were not presented. However, familial associations between schizophrenia and mood disorders are sufficiently strong to allow suspicion of a common genetic influence among some cases of each disease.36,39-42
Neuroleptic drugs are a potential confounding factor. All subjects with schizophrenia or mood disorder had been treated at some point with these drugs. Two subjects in each psychiatric group had not received neuroleptic drugs within 1 year of death, and these subjects had the same abnormalities as the others. Nonetheless, we cannot rule out the possibility that neuroleptic exposure accounts for the diminished arborization. Experimental studies of the effects of neuroleptic drugs on synaptic structures have focused on the striatum,43-45 where the density of dopamine type 2 receptors is greatest. In rats, 3 weeks of treatment with haloperidol increased the synaptic area or number in the striatum43,44 but not in the CA1 field of the hippocampus.43 Spine density in the striatum increased after 3 weeks44 but decreased after 6 months45 of haloperidol treatment. In layer VI of the medial prefrontal cortex, spine density decreased after 16 weeks of treatment with haloperidol (3 mg/kg per day)46 but was unchanged after 1 year at a lower dose (1.5 mg/kg per day).47 It is possible that neuroleptic drugs and psychiatric disease both contribute to dendritic remodeling and that this process contributes to the therapeutic and adverse effects of the drugs. It is also possible that institutionalization alone may affect dendritic structure, perhaps as a result of sensory deprivation. Furthermore, we cannot rule out the possibility that other treatments contributed to our results, either alone or in combination.
It must also be noted that rapid Golgi impregnation of human postmortem material is an imperfect procedure. Compared with material from experimental animals, dendritic trees appear less extensive; this has been attributed to postmortem delays, although no consistent differences have been found among the postmortem delays encountered in human tissue.48,49 Among the intervals that we encountered, there was no effect of postmortem delay on dendritic structure, the 3 groups were similar in terms of postmortem delay, and the differences in the extent of dendritic trees were not found in basilar dendrites or in neocortical neurons. Nonetheless, it would be worthwhile to repeat these studies using Golgi-Cox impregnation of fresh tissue, which may be less susceptible to postmortem delay.48 (Golgi-Cox impregnation is not applicable after prolonged fixation, while a minimum of 6 months' fixation is reportedly necessary for use of the rapid Golgi method.48) Finally, the impregnation of only a limited number of neurons is inherent to these methods; while allowing the tracing of processes, this restricts the possibility of random sampling of neurons.
Despite these limitations, this study demonstrates dramatic structural abnormalities in the subicular neurons of individuals with schizophrenia, which are shared by some individuals with mood disorders. The loss of dendrites and spines is consistent with current theories of the pathophysiologic function in schizophrenia, and its presence in the subiculum has important functional implications. Other methods should be employed to test this finding, and larger samples should be examined to evaluate the potential roles of family history and somatic treatments.
Accepted for publication December 17, 1999.
This study was supported by grants AG10638 and MH60877 (Dr Dwork), MH50727 and MH59342 (Jack Gorman, MD), AG08702 (Michael Shelanski, MD, PhD), and MH46745 (Dr Mann) from the National Institutes of Health, Bethesda, Md, and grants from the National Alliance for Research on Schizophrenia and Depression (Drs Rosoklija and Dwork), Great Neck, NY, the Theodore and Vada Stanley Foundation (Dr Rosoklija), Bethesda, and the US-Macedonia Joint Fund for Science and Technology (Drs Rosoklija and Dwork), Skopje, Republic of Macedonia, and by the Lieber Center for Schizophrenia Research at the Department of Psychiatry, College of Physicians & Surgeons of Columbia University, New York, NY.
Presented in part at the 24th Annual Meeting of the Society For Neuroscience, 1998, Los Angeles, Calif, November 7-12, 1998; the 75th Annual Meeting of the American Association of Neuropathologists, Portland, Ore, June 17-20, 1999; and the 25th Annual Meeting of the Society For Neuroscience, Miami Beach, Fla, October 23-28, 1999.
We thank Jack Gorman, MD, and Dolores Malaspina, MD, for review of the manuscript. The clinical record reviews were performed and reviewed by Eugene Alexander, PhD, Mariam Gibbon, PhD, Ronald Goldman, MD, Branislav Mancevski, MD, Ezra Susser, MD, DrPH, Isak Prohovnik, PhD, Christina Waniek, MD, Amy Wu, MD, and Zvi Zemishlany, MD. Mavis Kaufman, MD, and Dongmei Liu, MD, and the Neuropathology staff at Columbia University, New York, NY, contributed to the neuropathological reviews of these cases.
Reprints: Andrew J. Dwork, MD, Department of Neuroscience, Division of Neuropathology, New York State Psychiatric Institute, 1051 Riverside Dr, Unit 62, New York, NY 10032 (e-mail: email@example.com).
LD Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull.
1997;23437- 458Google ScholarCrossref
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- 818Google ScholarCrossref
NB Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry.
1995;52998- 1007Google ScholarCrossref
I Cortical pruning and the development of schizophrenia. Schizophr Bull.
1990;16567- 570Google ScholarCrossref
JW Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? the Feinberg hypothesis revisited. J Psychiatr Res.
1994;28239- 265Google ScholarCrossref
SB Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Ann Rev Neurosci.
1994;17341- 371Google ScholarCrossref
WG SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex.
1998;8261- 268Google ScholarCrossref
JQ Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry.
1995;152738- 748Google Scholar
PJ Size, shape, and orientation of neurons in the left and right hippocampus: investigation of normal asymmetries and alterations in schizophrenia. Am J Psychiatry.
1997;154812- 818Google Scholar
JQ Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. Proc Natl Acad Sci U S A.
1991;8810850- 10854Google ScholarCrossref
AJ Subicular MAP2 immunoreactivity is altered in schizophrenia. J Neurol Neurosurg Psychiatry. Google Scholar
E Dementia praecox, oder Gruppe der Schizophrenien. Leipzig, Germany Deuticke1911;
SR Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry.
1998;65446- 453Google ScholarCrossref
DA Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry.
2000;5765- 73Google ScholarCrossref
E Neuronal structure abnormality in the orbito-frontal cortex of schizophrenics. J Hirnforsch.
1991;32149- 158Google Scholar
PV Characteristics of the structural reorganization of the neurons of the reticular formation of human brain stem in schizophrenia. Zh Nevrol Psikhiatr Im S S Korsakova.
1989;8959- 61Google Scholar
DJ Reduced striatal spine size in schizophrenia: a postmortem ultrastructural study. Neuroreport.
1996;71214- 1218Google ScholarCrossref
RC Synaptic changes in the striatum of schizophrenic cases: a controlled postmortem ultrastructural study. Synapse.
1998;28125- 139Google ScholarCrossref
I Reliability of post-mortem chart diagnoses of schizophrenia and dementia. Schizophr Res.
1995;17221- 228Google ScholarCrossref
I Senile degeneration and cognitive impairment in chronic schizophrenia. Am J Psychiatry.
1988;1551536- 1543Google Scholar
JS Organization of neurons in the visual cortex, area 17, of the monkey (macaca mulatta
). J Comp Neurol.
1973;147455- 496Google ScholarCrossref
E Gehirndurchschnitte zur Erläuterung des Faserverlaufes. Wiesbaden, Germany Verlag von JF Bergmann1898;20- 21
DA Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat.
1953;87387- 406Google Scholar
RG An Introduction to the Bootstrap. New York, NY Chapman & Hall1993;202- 220
KA Mathematical Statistics: Basic Ideas and Selected Topics. San Francisco, Calif Holden-Day1977;209- 229
CE Variance Components. New York, NY John Wiley & Sons Inc1992;
TL Demonstration of axonal projections of neurons in the rat hippocampus and subiculum by intracellular injection of HRP. Brain Res.
1983;271201- 216Google ScholarCrossref
DL A direct projection from the perirhinal cortex (area 35) to the subiculum in the rat. Brain Res.
1983;269347- 351Google ScholarCrossref
KB Morphological evidence for a dopaminergic terminal field in the hippocampal formation of young and adult rat. Neuroscience.
1985;141039- 1052Google ScholarCrossref
JP A description of the amygdala-hippocampal interconnections in the macaque monkey. Exp Brain Res.
1986;64515- 526Google ScholarCrossref
U The perforant path projection from the medial entorhinal cortex layer III to the subiculum in the rat combined hippocampal-entorhinal cortex slice. Eur J Neurosci.
1998;101011- 1018Google ScholarCrossref
KS Accuracies and inaccuracies of the family history method: a multivariate approach. Acta Psychiatr Scand.
1996;93224- 234Google ScholarCrossref
D Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry.
1999;56133- 140Google ScholarCrossref
RW Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry.
1998;1551384- 1391Google Scholar
MS A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry.
1998;4488- 97Google ScholarCrossref
D The structure of psychosis: latent class analysis of probands from the Roscommon Family Study. Arch Gen Psychiatry.
1998;55492- 499Google ScholarCrossref
RW Subgenual prefrontal cortex reduction in first episode affective psychosis [abstract]. Biol Psychiatry.
JL Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A.
1998;9513290- 13295Google ScholarCrossref
E Patterns of illness in parent-child pairs both hospitalized for either schizophrenia or a major mood disorder. Psychiatry Res.
1991;3981- 87Google ScholarCrossref
L Congenital dermatoglyphic malformations in severe bipolar disorder. Psychiatry Res.
1998;78133- 140Google ScholarCrossref
II The New York High-Risk Project: prevalence and comorbidity of axis I disorders in offspring of schizophrenic parents at 25-year follow-up. Arch Gen Psychiatry.
1997;541096- 1102Google ScholarCrossref
D The risk for psychiatric illness in siblings of schizophrenics: the impact of psychotic and non-psychotic affective illness and alcoholism in parents. Acta Psychiatr Scand.
1996;9449- 55Google ScholarCrossref
H Morphometric study of synaptic patterns in the rat caudate nucleus and hippocampus under haloperidol treatment. Synapse.
1991;7253- 259Google ScholarCrossref
PM Synaptic plasticity in the rat striatum following chronic haloperidol treatment. Clin Neuropharmacol.
1992;15488- 500Google ScholarCrossref
RC The effect of chronic haloperidol treatment on dendritic spines in the rat striatum. Exp Neurol.
1997;146471- 478Google ScholarCrossref
VB Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats. Brain Res.
1985;34815- 20Google ScholarCrossref
FM Evidence for ultrastructural changes in cortical axodendritic synapses following long-term treatment with haloperidol or clozapine. Neuropsychopharmacology.
1991;5147- 155Google Scholar
SJ Golgi-Cox and rapid Golgi methods as applied to autopsied human brain tissue: widely disparate results. J Neuropathol Exp Neurol.
1982;41500- 507Google ScholarCrossref
Jr The Golgi rapid method in clinical neuropathology: the morphologic consequences of suboptimal fixation. J Neuropathol Exp Neurol.
1978;3713- 33Google ScholarCrossref