Differential activation of immune/inflammatory response-related co-expression modules in the hippocampus across the major psychiatric disorders.

The Stanley Neuropathology Consortium Integrative Database (SNCID, http://sncid.stanleyresearch.org) is a data-mining tool that includes 379 neuropathology data sets from hippocampus, as well as RNA-Seq data measured in 15 well-matched cases in each of four groups: schizophrenia, bipolar disorder (BPD), major depression (MD) and unaffected controls. We analyzed the neuropathology data from the hippocampus to identify those abnormalities that are shared between psychiatric disorders and those that are specific to each disorder. Of the 379 data sets, 20 of them showed a significant abnormality in at least one disorder as compared with unaffected controls. GABAergic markers and synaptic proteins were mainly abnormal in schizophrenia and the two mood disorders, respectively. Two immune/inflammation-related co-expression modules built from RNA-seq data from both schizophrenia and controls combined were associated with disease status, as well as negatively correlated with the GABAergic markers. The correlation between immune-related modules and schizophrenia was replicated using microarray data from an independent tissue collection. Immune/inflammation-related co-expression modules were also built from RNA-seq data from BPD cases or from MD cases but were not preserved when using data from control cases. Moreover, there was no overlap in the genes that comprise the immune/inflammation response-related modules across the different disorders. Thus, there appears to be differential activation of the immune/inflammatory response, as determined by co-expression of genes, which is associated with the major psychiatric disorders and which is also associated with the abnormal neuropathology in the disorders.

Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders.

Cytoarchitectural abnormalities have been described in the prefrontal cortex (PFC) of subjects with psychiatric disorders. We explored the possible genetic causalities that may underlie the cytoarchitectural abnormalities of calbindin-containing γ-aminobutyric acid (GABA)ergic neurons and perineuronal oligodendrocytes in the PFC of subjects with psychiatric disorders by converging results from genome-wide single-nucleotide polymorphism (SNP) scans for the traits and expression SNP (eSNP) associations. In the initial genome-wide scans, we identified several development- and apoptosis-related genes associated with the cytoarchitectural traits. Moreover, the susceptibility gene for bipolar disorder, PPP2R2C, was found to be associated with the number of perineuronal oligodendrocytes. Further eSNP analyses indicated that two novel candidate genes, RAB2A and SLC38A1, were associated with the density of calbindin-positive neurons and the number of perineuronal oligodendrocytes, respectively. Our findings may provide novel insights into the genetic causalities associated with cytoarchitectural abnormalities in the PFC of subjects with major psychiatric disorders as well as into the etiology of such disorders.

Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development.

The glucocorticoid receptor (GR) has a critical role in determining the brain's capacity to respond to stress, and has been implicated in the pathogenesis of psychiatric illness. We hypothesized that key changes in cortical GR occur during adolescence and young adulthood, at a time when individuals are at increased risk of developing schizophrenia, bipolar disorder and major depression. We investigated the mRNA and protein expression of GR in the dorsolateral prefrontal cortex across seven developmental time points from infancy to adulthood. GR mRNA expression, determined by microarray and quantitative real-time PCR, was lowest in neonates and peaked around young adulthood. Western blotting revealed two dynamic patterns of GRα protein expression across the lifespan, with N-terminal variants displaying differing unique patterns of abundance. GRα-A and a 67-kDa GRα isoform mirrored mRNA trends and peaked in toddlers and late in adolescence, whereas a 40-kDa isoform, very likely a GRα-D variant, peaked in neonates and decreased across the lifespan. GRα protein was localized to pyramidal neurons throughout life and most strikingly in young adulthood, but to white matter astrocytes only in neonates and infants (<130 days). These results suggest that the neonatal and late adolescent periods represent critical windows of stress pathway development, and highlight the importance of white matter astrocytes and pyramidal neurons, respectively, at these stages of cortical development. Evidence of dynamic patterns of GR isoform expression and cellular localization across development strengthens the hypothesis that windows of vulnerability to stress exist across human cortical development.

Correlation analysis between genome-wide expression profiles and cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders.

Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n=14; bipolar disorder, n=13; depression, n=12 and controls n=15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders.

p11 is up-regulated in the forebrain of stressed rats by glucocorticoid acting via two specific glucocorticoid response elements in the p11 promoter.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric disorders. Despite the extensive study of the neurobiological correlates of this disorder, the underlying mechanisms of PTSD are still poorly understood. Recently, a study demonstrated that dexamethasone (Dex), a synthetic glucocorticoid, can up-regulate p11, known as S100A10-protein which is down-regulated in patients with depression, (Yao et al., 1999; Huang et al., 2003) a common comorbid disorder in PTSD. These observations led to our hypothesis that traumatic stress may alter expression of p11 mediated through a glucocorticoid receptor. Here, we demonstrate that inescapable tail shock increased both prefrontal cortical p11 mRNA levels and plasma corticosterone levels in rats. We also found that Dex up-regulated p11 expression in SH-SY5Y cells through glucocorticoid response elements (GREs) within the p11 promoter. This response was attenuated by either RU486, a glucocorticoid receptor (GR) antagonist or mutating two of three glucocorticoid response elements (GRE2 and GRE3) in the p11 promoter. Finally, we showed that p11 mRNA levels were increased in postmortem prefrontal cortical tissue (area 46) of patients with PTSD. The data obtained from our work in a rat model of inescapable tail shock, a p11-transfected cell line and postmortem brain tissue from PTSD patients outline a possible mechanism by which p11 is regulated by glucocorticoids elevated by traumatic stress.

Postnatal alterations in dopaminergic markers in the human prefrontal cortex.

Dopamine in the prefrontal cortex plays a critical role in normal cognition throughout the lifespan and has been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia and attention deficit disorder. Little is known, however, about the postnatal development of the dopaminergic system in the human prefrontal cortex. In this study, we examined pre- and post-synaptic markers of the dopaminergic system in postmortem tissue specimens from 37 individuals ranging in age from 2 months to 86 years. We measured the levels of tyrosine hydroxylase, the rate limiting enzyme in dopamine biosynthesis, using Western immunoblotting. We also examined the gene expression of the three most abundant dopamine receptors (DARs) in the human prefrontal cortex: DAR1, DAR2 and DAR4, by in situ hybridization. We found that tyrosine hydroxylase concentrations and DAR2 mRNA levels were highest in the cortex of neonates. In contrast, the gene expression of DAR1 was highest in adolescents and young adults. No significant changes across age groups were detected in mRNA levels of DAR4. Both DAR1 and DAR2 mRNA were significantly lower in the aged cortex. Taken together, our data suggest dynamic changes in markers of the dopamine system in the human frontal cortex during postnatal development at both pre-and post-synaptic sites. The peak in DAR1 mRNA levels around adolescence/early adulthood may be of particular relevance to neuropsychiatric disorders such as schizophrenia in which symptoms manifest during the same developmental period.

BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan.

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (trkB) influence neuronal survival, differentiation, synaptogenesis, and maintenance. Using in situ hybridization we examined the spatial and temporal expression of mRNAs encoding these proteins during diverse stages of life in the human hippocampus and inferior temporal cortex. We examined six postnatal time points: neonatal (1-3 months), infant (4-12 months), adolescent (14-18 years), young adult (20-24 years), adult (34-43 years), and aged (68-86 years). Within the hippocampus, levels of BDNF mRNA did not change significantly with age. However, levels of both the full-length form of trkB (trkB TK+) mRNA and the truncated form of trkB (trkB TK-) decreased over the life span (p < 0.05). In the temporal cortex, BDNF and trkB TK+ mRNA levels were highest in neonates and decreased with age (r = -0.4 and r = -0.7, respectively, both p < 0.05). In contrast, TrkB TK- mRNA levels remained constant across the life span in the temporal cortex. The peak in both BDNF and trkB TK+ mRNA expression in the neonate temporal cortex differs from that previously described for the frontal cortex where both mRNAs peak in expression during young adulthood. The increase in BDNF and trkB TK+ mRNA in the temporal cortex of the neonate suggests that neurotrophin signaling is important in the early development of the temporal cortex. In addition, since BDNF and both forms of its high affinity receptor are expressed throughout the development, maturation, and aging of the human hippocampus and surrounding neocortex they are likely to play roles not only in early growth but also in maintenance of neurons throughout life.

Transcriptome sequencing of the choroid plexus in schizophrenia.

The choroid plexus (CP) has a key role in maintaining brain homeostasis by producing cerebrospinal fluid (CSF), by mediating transport of nutrients and removing metabolic products from the central nervous system and by responding to peripheral inflammatory signals. Although abnormal markers of immune response and inflammation are apparent in individuals with schizophrenia, the CP of these individuals has not been characterized. We therefore sequenced mRNA from the CP from two independent collections of individuals with schizophrenia and unaffected controls. Genes related to immune function and inflammation were upregulated in both collections. In addition, a co-expression module related to immune/inflammation response that was generated by combining mRNA-Seq data from both collections was significantly associated with disease status. The immune/inflammation-related co-expression module was positively correlated with levels of C-reactive protein (CRP), cortisol and several immune modulator proteins in the serum of the same individuals and was also positively correlated with CRP, cortisol and pro-inflammatory cytokines in the frontal cortex of the same individuals. In addition, we found a substantial number of nodes (genes) that were common to our schizophrenia-associated immune/inflammation module from the pooled data and a module we generated from lippopolysaccharides-treated mouse model data. These results suggest that the CP of individuals with schizophrenia are responding to signals from the periphery by upregulating immune/inflammation-related genes to protect the brain and maintain the homeostasis but nevertheless fails to completely prevent immune/inflammation related changes in the brain.

Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia.

Recent studies have shown a decrease in glial number and glial fibrillary acidic protein (GFAP) levels in the frontal and cingulate cortices of individuals with mood disorders and schizophrenia. In an attempt to verify and expand these findings we examined GFAP messenger ribonucleic acid (mRNA) levels in postmortem sections of the anterior cingulate cortex (ACC) from the Stanley Neuropathology Consortium (SNC). The consortium consists of 15 cases in each of four groups (schizophrenia, bipolar disorder, non-psychotic depression and unaffected controls). By in situ hybridization, we found higher levels of GFAP mRNA in white matter and at the pial surface as compared with gray matter levels in all cases. In the white matter of ACC we detected a significant effect of diagnosis (P<0.04) with GFAP mRNA levels decreased in individuals with schizophrenia and bipolar disorder as compared with normal controls. In the gray matter there was a significant effect of layer (P<0.01) with the highest levels of GFAP mRNA in layer VI in all groups. As in the white matter, the mean GFAP mRNA levels were decreased in individuals with schizophrenia and bipolar disorder as compared with the unaffected controls, however the difference failed to reach statistical significance. Thus, astrocytes positive for GFAP may contribute to the decrease in glial density previously described in subjects with major mental illness, however the relative contribution of astrocytes may vary with diagnosis.

Expression of estrogen receptor alpha exon-deleted mRNA variants in the human and non-human primate frontal cortex.

Although estrogen receptor alpha (ERalpha) mRNA has been detected in the primate frontal cortex, the types of ERalpha transcripts expressed, including exon-deleted variants (Delta), have not been determined in the monkey or human frontal cortex. Because the types of ERalpha mRNA expressed in brain could define neuronal responses to estrogens, we examined the transcript pool of ERalpha mRNAs expressed in normal adult and developing human and macaque frontal cortex. We reverse transcribed total RNA from the postmortem frontal cortex of 29 normal adult humans, 12 rhesus macaques, and 19 people ranging from infants to adults and employed two rounds of nested polymerase chain reaction (PCR) to generate ERalpha products spanning the coding domain. In a third nested PCR, we used primers specific for novel sequences of exon-exon junctions created when whole exons are missing. By sequencing PCR products, we detected 60 instances of 12 distinct DeltaERalpha mRNAs in adult humans and 94 instances of 13 distinct DeltaERalpha mRNAs in monkeys in differing patterns from one individual to another. In adult humans, 83% of individuals expressed at least 1 DeltaERalpha mRNA variant, and 100% of the monkeys expressed at least 1 DeltaERalpha mRNA variant. The single Delta2, Delta5, and Delta7 variants were frequently expressed in both human and monkey frontal cortex, Delta3 variants were rare in both species, and Delta6 variants were more frequently expressed in monkeys. In both species, we detected double, triple and quadruple Deltas, but these were less common than single Deltas. The pattern of human variant expression did not appear to change dramatically as a function of age. These findings imply the potential to produce different ERalpha proteins in frontal cortex, possibly with altered structure and function which may have physiological relevance for gene transcription by virtue of altered functional interactions with each other, other steroid hormone receptors, and genomic DNA.

The morphology of relay neurons in the dorsal lateral geniculate nucleus of the marsupial brush-tailed possum (Trichosurus vulpecula).

The retinal terminal zones and the morphology of relay neurons within the dorsal lateral geniculate nucleus (LGNd) of the brush-tailed possum (Trichosurus vulpecula) have been investigated with horseradish peroxidase (HRP) tracing techniques. Anterograde transport of HRP from the retina confirmed previous descriptions of the laminar distribution of retinal afferents in this nucleus. In addition, it was found that lamina III consists of two adjacent bands (IIIa and IIIb) of contralateral retinal input, separated by a terminal-free zone 20-40 micron wide. This zone is not apparent with Nissl or fibre stains. Relay neurons in the LGNd were retrogradely filled following cortical injections of HRP, and two classes (A and B) were distinguished. Class A neurons are found in the alpha portion of the LGNd (laminae I, II, III, and IV) and class B neurons in the beta portion (laminae V, VI, and VII). Class A cells are more densely packed and have shorter and more numerous dendrites, less-extensive dendritic arbors, and thicker axons than class B cells. No significant differences were found between the two classes in perikaryal size or thickness of proximal dendrites. Neurons in each lamina of the nucleus have dendritic arbors which ramify extensively within adjacent laminae, except cells in lamina IIIb, which have relatively few dendrites that cross into the cell-free zone and lamina IV.

Disruption of developmental timing in the albino rat retina.

We have examined the spatial and temporal gradients of two developmental processes in albino and pigmented rats: outer plexiform layer (OPL) development, and rate of cell production. The OPL first appears as a thin, discontinuous break in the cytoblast layer that is frequently interrupted by the profiles of migrating neuro- and glioblasts. In both strains, this occurs in an area temporal to the optic disc that corresponds to the eventual site of peak ganglion cell density, but is not located along the line of nasotemporal division. The OPL is first evident at P5 in pigmented animals, but its appearance in albino animals is delayed approximately 30 hours, and its development appears to follow a flatter spatial gradient than in pigmented animals. In pigmented animals OPL formation is complete over most of the retina by P10, but in albino animals at this age it is yet to be completely formed at any retinal location. Reductions in mitotic activity are also first evident in temporal retina, but unlike OPL development, appear to follow the same temporal-spatial gradient in both strains. Reductions in temporal retina are obvious by P4, and mitotic activity has ceased altogether in midtemporal retina by P6 and throughout most remaining retinal regions by P8. Thus, the initial reduction of mitotic activity precedes the onset of OPL formation in both strains, but OPL development lags behind the reduction of mitotic activity to a greater extent in albino than in pigmented animals. Some aspects of differentiation within the inner nuclear layer (INL) were also examined. Just prior to the time of the onset of OPL formation, three distinct sublaminae are apparent in the INL. Cells in the innermost sublamina appear to be in an early stage of differentiation. Cells in the middle sublamina appear to be postmigratory, but have not yet begun to differentiate. Cells in the outermost sublamina have the appearance of migrating neuroblasts. At least some of these outer cells appear to migrate across the developing OPL to the outer nuclear layer, since the outermost sublamina becomes thinner and eventually disappears at the same time that the OPL becomes a continuous, uninterrupted plexiform layer. Cells of the middle sublamina apparently begin differentiation at about the time that this migration is complete. Although this sequence is the same in both albino and pigmented strains, its onset is delayed in albino animals by the same amount as the onset of OPL formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Transient subcortical connections of inferior temporal areas TE and TEO in infant macaque monkeys.

As part of a long-term study designed to examine the ontogeny of visual memory in monkeys and its underlying neural circuitry, we have examined the subcortical connections of the inferior temporal cortex in infant monkeys and compared them to those previously described in adult monkeys (Webster et al. [1993] J. Comp. Neurol. 335:73-91). Inferior temporal areas TEO and TE were injected with wheat germ agglutinin conjugated to horseradish peroxidase and tritiated amino acids, respectively, or vice versa, in 1-week-old (N = 6) and 3-4-year-old (N = 6) Macaca mulatta, and the distributions of labeled cells and terminals were examined in subcortical structures. Although the connections of inferior temporal cortex with subcortical structures were found to be similar in infant and adult monkeys, several projections appear to undergo refinement during development. Quantitative analysis showed that 1) whereas the projection from TE to the superior colliculus is consistent (5 of 5 cases) and widespread in infants, it is less reliable (2 of 7 cases) and limited in areal extent in adults; 2) although the projections from TE to nucleus medialis dorsalis and the tail of the caudate are present in infants and adults, they are reduced in adults; and 3) TEO receives input from the dorsal lateral geniculate nucleus in both infants and adults, but the number of cells giving rise to this projection is lower in adults. There was also a suggestion that TE projects to nucleus paracentralis in infants (2 of 5 cases) but not in adults (0 of 7 cases). No differences between infants and adults were apparent in other subcortical connections, including those with the pulvinar, reticular nucleus, claustrum, and putamen.

Subcortical connections of inferior temporal areas TE and TEO in macaque monkeys.

To investigate the subcortical connections of inferior temporal cortex, we injected its anterior and posterior portions (Bonin and Bailey's cytoarchitectonic areas TE and TEO, respectively) in 6 rhesus monkeys with retrograde and anterograde tracers. The results indicate that both areas TE and TEO receive nonreciprocal inputs from several thalamic nuclei, including paracentralis, ventralis anterior, centralis, and limitans, and that TE also receives input from reuniens. Additional nonreciprocal inputs to both areas arise from the hypothalamus, basal nucleus of Meynert, dorsal and median raphe, locus coeruleus, and reticular formation. TE and TEO are reciprocally connected with the lateral, medial, and inferior nuclei of the pulvinar and with the ventral portion of the claustrum. The main subcortical nonreciprocal output from TE and TEO is to the striatum and from TEO to the superior colliculus. TE also sends a very limited projection to nucleus medialis dorsalis magnocellularis of the thalamus. Although the connections of areas TE and TEO are overlapping in most subcortical structures, they are partially segregated in the pulvinar, the reticular nucleus of the thalamus, and the striatum. Specifically, relative to those of TE, the projections of TEO are located more laterally in the medial, lateral, and inferior nuclei of the pulvinar, more ventrally in the reticular nucleus, and more caudally in both the ventral putamen and tail and head of the caudate nucleus.

Abnormal pigmentation and unusual morphogenesis of the optic stalk may be correlated with retinal axon misguidance in embryonic Siamese cats.

Studies of albino rodents have shown that an absence of pigment in the developing optic stalk may alter the position of the first retinal fibers that grow toward the brain, thereby disrupting the gross topographic relationship of fibers in the nerve (Silver and Sapiro: J. Comp. Neurol. 202:521-538, '81). The abnormalities associated with albinism are more extensive in the Siamese cat than-in previously studied species. Therefore, any abnormalities in differentiation of the stalk and axon guidance may be more readily detected. To investigate the guidance and/or misguidance of optic axons, light and electron microscope analyses were made of serial sections through the optic stalk in normally pigmented and Siamese fetal cats. On E20, before axons enter the optic stalk, the only clear morphological distinction between Siamese and normal cats is the distribution of pigment in the stalk. Pigment is found in the dorsal stalk cells of the normal cat for 200 microns from the optic disc. Although the retinal pigment epithelium of the Siamese optic stalk. By E23 axons invade the ventral optic stalk in both strains. Concurrent with the early stages of axonal exit from the retina, there is complete separation of the stalk's dorsal and ventral tiers. As the cleavage occurs, basal lamina invaginates into the zone of separation following along the plane of the old lumen. The ventral stalk fills with axons while the dorsal tier is shed gradually. In contrast, in the Siamese cat, dorsal stalk cells are not sloughed off properly and instead are incorporated ectopically into the nerve. Basal lamina invagination is irregular. Axons do not fill the Siamese stalk symmetrically but enter the region of ectopic cells, which in turn disrupts gross fiber position. Usually, in the mutant, axons originating from the retina temporal to the optic fissure are those that invade the dorsal tier of ectopic cells. The altered position of optic axons in the mutant stalk may provide an explanation for the chiasmatic misrouting of optic axons in this species.

Visual cortical projections and chemoarchitecture of macaque monkey pulvinar.

We investigated the patterns of projections from the pulvinar to visual areas V1, V2, V4, and MT, and their relationships to pulvinar subdivisions based on patterns of calbindin (CB) immunostaining and estimates of visual field maps (P(1), P(2) and P(3)). Multiple retrograde tracers were placed into V1, V2, V4, and/or MT in 11 adult macaque monkeys. The inferior pulvinar (PI) was subdivided into medial (PI(M)), posterior (PI(P)), central medial (PI(CM)), and central lateral (PI(CL)) regions, confirming earlier CB studies. The P(1) map includes PI(CL) and the ventromedial portion of the lateral pulvinar (PL), P(2) is found in ventrolateral PL, and P(3) includes PI(P), PI(M), and PI(CM). Projections to areas V1 and V2 were found to be overlapping in P(1) and P(2), but those from P(2) to V2 were denser than those to V1. V2 also received light projections from PI(CM) and, less reliably, from PI(M). Neurons projecting to V4 and MT were more abundant than those projecting to V1 and V2. Those projecting to V4 were observed in P(1), densely in P(2), and also in PI(CM) and PI(P) of P(3). Those projecting to MT were found in P(1)- P(3), with the heaviest projection from P(3). Projections from P(3) to MT and V4 were mainly interdigitated, with the densest to MT arising from PI(M) and the densest to V4 arising from PI(P) and PI(CM). Because the calbindin-rich and -poor regions of P(3) corresponded to differential patterns of cortical connectivity, the results suggest that CB may further delineate functional subdivisions in the pulvinar.

Localization of epidermal growth factor receptors and putative neuroblasts in human subependymal zone.

Studies in rodents and monkeys suggest that neuronal precursor cells continue to exist and differentiate well into adulthood in these species. These results challenge the long held assumption that neurogenesis does not occur in the postnatal human brain. We examined the rostral subependymal zone (SEZ) of postnatal human brain for expression of cell phenotypic markers that have been associated with neuronal precursors and neuroblasts in rodent brain. We found epidermal growth factor receptor (EGF-R) mRNA and protein to be expressed in infant, teen, young adult, and adult human SEZ. Some SEZ cells expressed the polysialic acid form of neural cell adhesion molecule (PSA-NCAM), characteristic of migrating neuroblasts, as well as class III beta-tubulin and Hu protein, characteristic of neuroblasts and early neurons. These neuroblast-like cells were negative for glial fibrillary acidic protein (GFAP), 2;,3;-cyclic nucleotide 3;-phosphohydrolase (CNPase), and vimentin, suggesting that they were not differentiating as glia. Our results show that neuroblast-like cells exist in the human SEZ and support the theory that SEZ of postnatal human brain has neurogenic potential.

Neurofilament protein is differentially distributed in subpopulations of corticocortical projection neurons in the macaque monkey visual pathways.

Previous studies of the primate cerebral cortex have shown that neurofilament protein is present in pyramidal neuron subpopulations displaying specific regional and laminar distribution patterns. In order to characterize further the neurochemical phenotype of the neurons furnishing feedforward and feedback pathways in the visual cortex of the macaque monkey, we performed an analysis of the distribution of neurofilament protein in corticocortical projection neurons in areas V1, V2, V3, V3A, V4, and MT. Injections of the retrogradely transported dyes Fast Blue and Diamidino Yellow were placed within areas V4 and MT, or in areas V1 and V2, in 14 adult rhesus monkeys, and the brains of these animals were processed for immunohistochemistry with an antibody to nonphosphorylated epitopes of the medium and heavy molecular weight subunits of the neurofilament protein. Overall, there was a higher proportion of neurons projecting from areas V1, V2, V3, and V3A to area MT that were neurofilament protein-immunoreactive (57-100%), than to area V4 (25-36%). In contrast, feedback projections from areas MT, V4, and V3 exhibited a more consistent proportion of neurofilament protein-containing neurons (70-80%), regardless of their target areas (V1 or V2). In addition, the vast majority of feedback neurons projecting to areas V1 and V2 were located in layers V and VI in areas V4 and MT, while they were observed in both supragranular and infragranular layers in area V3. The laminar distribution of feedforward projecting neurons was heterogeneous. In area V1, Meynert and layer IVB cells were found to project to area MT, while neurons projecting to area V4 were particularly dense in layer III within the foveal representation. In area V2, almost all neurons projecting to areas MT or V4 were located in layer III, whereas they were found in both layers II-III and V-VI in areas V3 and V3A. These results suggest that neurofilament protein identifies particular subpopulations of corticocortically projecting neurons with distinct regional and laminar distribution in the monkey visual system. It is possible that the preferential distribution of neurofilament protein within feedforward connections to area MT and all feedback projections is related to other distinctive properties of these corticocortical projection neurons.

Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia.

Synaptophysin and growth associated protein-43 (GAP-43) are synaptic proteins colocalized to the presynaptic terminal, and involved in regulating transmitter release and synaptic plasticity. Recent studies have proposed an alteration in the number of synapses in the brains of individuals with schizophrenia. As a corollary, we hypothesized that there may be an alteration in the level of mRNAs that code for synaptic proteins in brains of patients with schizophrenia. Using in situ hybridization, we investigated the levels of synaptophysin and GAP-43 mRNA in the medial temporal lobe of 10 normal subjects, 11 subjects with schizophrenia and 10 psychiatric control subjects. Synaptophysin mRNA levels were significantly reduced in several hippocampal subfields in both the schizophrenic and psychiatric control groups. GAP-43 mRNA levels were not significantly reduced in either group. The implications of these findings are discussed in relation to neuroleptic treatment and the pathophysiology of mental illness.