Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model.

Schizophrenia (SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 and DAXX. To characterize the contribution of these factors to the developmental perturbation hypothesized to underlie SZ, lentiviral vectors carrying short hairpin RNA interference (shRNAi) for HDAC1 and DAXX were used. In the hippocampal GABA neuron culture model, HiB5, transduction with HDAC1 shRNAi showed a 40% inhibition of HDAC1 mRNA and a 60% inhibition of HDAC1 protein. GAD67, a enzyme associated with GABA synthesis, was increased twofold (mRNA); the protein showed a 35% increase. The expression of DAXX, a co-repressor of HDAC1, was not influenced by HDAC1 inhibition. Transduction of HiB5 cells with DAXX shRNAi resulted in a 30% inhibition of DAXX mRNA that translated into a 90% inhibition of DAXX protein. GAD1 mRNA was upregulated fourfold, while its protein increased by ~30%. HDAC1 expression was not altered by inhibition of DAXX. However, a physical interaction between HDAC1 and DAXX was demonstrated by co-immunoprecipitation. Inhibition of HDAC1 or DAXX increased expression of egr-1, transcription factor that had previously been shown to regulate the GAD67 promoter. Our in vitro results point to a key role of both HDAC1 and DAXX in the regulation of GAD67 in GABAergic HiB5 cells, strongly suggesting that these epigenetic/transcription factors contribute to mechanisms underlying GABA cell dysfunction in SZ.

The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia.

Post-mortem studies conducted over the past 15 years suggest that apoptosis could play a role in the pathophysiology of bipolar disorder (BD) and, to a lesser degree, schizophrenia (SZ). To test this hypothesis, we have performed a post hoc analysis of an extant gene expression profiling database obtained from the hippocampus using a novel methodology with improved sensitivity. Consistent with the working hypothesis, BDs showed a marked upregulation of 19 out of 44 apoptosis genes; however, contrary to the hypothesis, the SZ group showed a downregulation of genes associated with apoptotic injury and death. These changes in the regulation of apoptosis genes were validated using quantitative RT-PCR. Additionally, antioxidant genes showed a marked downregulation in BDs, suggesting that accumulation of free radicals might occur in the setting of a previously reported decrease of the electron transport chain in this disorder. Overall, the changes seen in BDs and SZs do not appear to be related to exposure to either neuroleptics or mood stabilizers. We conclude that fundamental differences in the genetic regulation of apoptosis and antioxidant genes may help discriminate between the pathophysiology of BD and SZ and potentially point to new treatment strategies that are specific for each disorder.

Mapping of hippocampal gene clusters regulated by the amygdala to nonlinkage sites for schizophrenia.

A recent study using a 'partial' rodent model of schizophrenia has employed amygdalar activation to induce reported changes in the expression of hippocampal genes associated with metabolic and signaling pathways in response to amygdalar activation. The amygdalo-hippocampal pathway plays a central role in the regulation of the stress response and emotional learning. In the current study, we have performed a chromosome mapping analysis to determine whether genes showing changes in response to environmental stress may form clusters and, if so, whether they might show a topographical association with linkage sites for schizophrenia. When the hippocampal genes showing changes in expression were topographically mapped on specific rat chromosomes, significant clustering was observed on chromosomes 1, 4 and 8, although chromosome 1 showed the largest amount of clustering. When these same rodent genes were mapped to human chromosomes, most of the genes found on chromosome 1 in rat mapped to chromosome 11 in human. The vast majority of the genes showing changes in regulation were excluded from known linkage sites for schizophrenia. Based on these findings, we postulate that environmental factors may contribute to the endophenotype for schizophrenia through the activation and/or deactivation of specific genetic clusters, ones that do not appear to be directly associated with susceptibility genes for this disorder.

Acute amygdalar activation induces an upregulation of multiple monoamine G protein coupled pathways in rat hippocampus.

A "partial" rodent model for schizophrenia has been used to characterize the regulation of hippocampal genes in response to amygdalar activation. At 96 h after the administration of picrotoxin into the basolateral nucleus, we have observed an increase in the expression of genes associated with 18 different monoamine (ie adrenergic alpha 1, alpha 2 and beta 2, serotonergic 5HT5b and 5HT6, dopamine D4 and muscarinic m1, m2 and m3) and peptide (CCK A and B, angiotensin 1A, mu and kappa opiate, FSH, TSH, LH, GNRH, and neuropeptide Y) G-protein coupled receptors (GPCRs). These latter receptors are associated with three different G protein signaling pathways (Gq, Gs, and Gi) in which significant changes in gene expression were also noted for adenylate cyclase (AC4), phosphodiesterase (PDE4D), protein kinase A (PKA), and protein kinase C (PKC). Quantitative RT-PCR was used to validate the results and demonstrated that there were predictable increases of three GPCRs selected for this analysis, including the dopamine D4, alpha 1b, and CCK-B receptors. Eight out of the nine monoamine receptors showing these changes have moderate to high affinity for the atypical antipsychotic, clozapine. Taken together, these results suggest that amygdalar activation may play a role in the pathophysiology and treatment of psychosis by regulating the activity of multiple GPCR and metabolic pathways in hippocampal cells.

GluR5,6,7 subunit immunoreactivity on apical pyramidal cell dendrites in hippocampus of schizophrenics and manic depressives.

Recent postmortem studies have suggested that changes in the regulation of kainate-sensitive glutamate receptors (kainate receptors) in the hippocampus may play a role in schizophrenia. To explore this possibility further, the distribution of immunoreactivity (IR) for the GluR5,6,7 subunits of the KR was assessed in a cohort consisting of 15 normal controls, 15 schizophrenics, and 9 manic depressives matched for age and postmortem interval (PMI). Cross sections of hippocampus showed abundant GluR5,6,7-IR on apical dendrites of pyramidal neurons in the stratum radiatum and stratum moleculare. In normal controls, both the numerical and length density of IR dendrites were much higher in sector CA2 than in sectors CA3 or CA1. When data for the individual groups were separately examined, the schizophrenics showed a 30-35% reduction in the density of GluR5,6,7-IR dendrites found in both stratum radiatum and stratum moleculare of sectors CA3 and CA2, as well as proximal and middle portions of CA1. In CA2, the magnitude of this decrease in schizophrenia was 2.5 times larger than that seen in any of the other sectors. For the manic depressive group, no significant differences were observed in any sectors or laminae examined. The potential confounding effects of either age, PMI, or neuroleptic exposure do not explain the reduced density of IR dendrites detected in the schizophrenic group. Taken together, the preferential reduction of GluR5,6,7-IR observed on apical dendrites of pyramidal neurons is consistent with a functional downregulation of the kainate receptor in the hippocampus of schizophrenic brain.

Effects of pre- and postnatal corticosterone exposure on the rat hippocampal GABA system.

Several lines of evidence have implicated prenatal stress and the hippocampal GABA system in the pathophysiology of schizophrenia, and prenatal stress is believed to increase the risk for schizophrenia through alterations of this neurotransmitter. To explore this hypothesis, we treated male rats pre- and/or postnatally (P48 and P60) with either corticosterone (CORT) or vehicle to establish three study groups: VVV, receiving vehicle at all three time points; VCC, receiving vehicle prenatally and CORT at both postnatal timepoints; and CCC, receiving CORT at all three timepoints. Animals were sacrificed at either 24 h or 5 days after final injection and examined for mRNA levels of GAD65, GAD67, and the GABA(A) receptor subunits alpha2 and gamma2. At 24 h, GAD65 mRNA was decreased in CA1, CA2, CA4, and dentate gyrus (DG) of VCC rats; this effect was either decreased or reversed in CCC-treated animals. No effect was detected in GAD67 mRNA at 24 h. At 5 days, CORT treatment increased GAD67 mRNA levels in CA1, CA3, and DG. Prenatal treatment with CORT was associated with increased responsiveness only in CA3 and DG. For the GABAA receptor, alpha2 subunit mRNA did not show any change in response to CORT treatment, while that for the gamma2 subunit was decreased in CA2 of both VCC- and CCC-treated animals. Consistent with gamma2 subunit mRNA decreases, benzodiazepine (BZ) receptor binding activity was decreased in CA2 with CORT treatment. Prenatal CORT exposure neither increased nor decreased this effect. These results demonstrate that CORT administration is associated with a complex regulation of mRNA expression for pre- and postnatal aspects of the hippocampal GABA system. Under these conditions, prenatal exposure to CORT may sensitize some of these effects, but does not fundamentally alter the nature of this response.

The density of pyramidal and nonpyramidal neurons in anterior cingulate cortex of schizophrenic and bipolar subjects.

BACKGROUND: A recent study reported a decreased density of nonpyramidal neurons (NPs) in layer II of the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of schizophrenic brain that was most pronounced in schizoaffective subjects. Our study assessed whether a decrease of NPs in ACCx may show a stronger covariation with affective disorder. A cohort consisting of 12 normal control (CONs), 11 schizophrenic, and 10 bipolar subjects matched for age and postmortem interval (PMI) has been analyzed. METHODS: A two-dimensional technique was employed for counting cells in a large x,y sampling column that extended across layers I through VI of ACCx. RESULTS: There was a 27% reduction in the density of NPs in layer II of the bipolar group, whereas in the schizophrenic group, this density was 16.2% lower. There were no differences in NPs in layers III through VI of either the schizophrenic or bipolar group. Both groups also showed modest decreases of PNs in the deeper laminae; however, these differences were only significant in layer IV of the schizophrenic subjects. The density of glial cells was similar across the control, schizophrenic, and bipolar groups. An Abercrombie correction for cell size did not alter the nature of the results. Subjects both with and without neuroleptic exposure showed a lower density of NPs in layer II of bipolar subjects or PNS in deeper laminae of schizophrenic subjects. CONCLUSIONS: Overall, the findings reported here suggest that local circuit cells in layer II of ACCx may be decreased in bipolar disorder, whereas projection neurons in deeper laminae are decreased in schizophrenia.

GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder.

A core component to corticolimbic circuitry is the GABAergic interneuron. Neuroanatomic studies conducted over the past century have demonstrated several subtypes of interneuron defined by characteristic morphological appearances in Golgi-stained preparations. More recently, both cytochemical and electrophysiological techniques have defined various subtypes of GABA neuron according to synaptic connections, electrophysiological properties and neuropeptide content. These cells provide both inhibitory and disinhibitory modulation of cortical and hippocampal circuits and contribute to the generation of oscillatory rhythms, discriminative information processing and gating of sensory information within the corticolimbic system. All of these functions are abnormal in schizophrenia. Recent postmortem studies have provided consistent evidence that a defect of GABAergic neurotransmission probably plays a role in both schizophrenia and bipolar disorder. Many now believe that such a disturbance may be related to a perturbation of early development, one that may result in a disturbance of cell migration and the formation of normal lamination. The ingrowth of extrinsic afferents, such as the mesocortical dopamine projections, may "trigger" the appearance of a defective GABA system, particularly under stressful conditions when the modulation of the dopamine system is likely to be altered. Based on the regional and subregional distribution of changes in GABA cells in schizophrenia and bipolar disorder, it has been postulated that the basolateral nucleus of the amygdala may contribute to these abnormalities through an increased flow of excitatory activity. By using "partial" modeling, changes in the GABA system remarkably similar to those seen in schizophrenia and bipolar disorder have been induced in rat hippocampus. In the years to come, continued investigations of the GABA system in rodent, primate and human brain and the characterization of changes in specific phenotypic subclasses of interneurons in schizophrenia and bipolar disorder will undoubtedly provide important new insights into how the integration of this transmitter system may be altered in neuropsychiatric disease.

Two-dimensional versus three-dimensional cell counting: a practical perspective.

In recent years, it has been argued by some neuroanatomists that three-dimensional (3-D) counting approaches must be used in studies of neural systems, so that 'unbiased' counts of neurons can be obtained. By contrast, two-dimensional (2-D) cell-counting methods are said to be 'assumption-based' and to yield inaccurate results. Working from the premise that all scientific methodologies are assumption-based and suffer from inherent biases, the current review considers the relative strengths and weaknesses of 2-D versus 3-D counting approaches. This comparison is from the standpoint of predictive performance with respect to bias, variance and fidelity to the actual spatial arrangements of cells in the tissue under study. When these considerations are taken, together with the human resources that are required in using either methodology, 2-D methods offer more practical alternatives that might even provide more scientifically accurate estimates compared with their 3-D counterparts.

Amygdalar activation alters the hippocampal GABA system: "partial" modelling for postmortem changes in schizophrenia.

Abnormalities in amygdala and hippocampus have been shown to coexist in schizophrenia (SZ). In the hippocampus, compelling evidence suggests that a disruption of GABA neurotransmission is present mainly in sectors CA4, CA3, and CA2. The amygdala sends important inputs to the hippocampus and is also believed to have a defective GABA system in schizophrenia. To explore the possibility that changes in the hippocampal GABAergic system could be related to an increased inflow of activity originating in the amygdala, a "partial" animal model has been developed. In awake, freely moving, rats a GABA(A) receptor antagonist was infused locally into the basolateral nuclear complex of the amygdala (BLn). Within 2 hours, a decreased density of both the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD(65) and GAD(67)) -immunoreactive (IR) terminals was detected on neuron somata in sectors CA3 and CA2, but not in CA1, CA3, or dentate gyrus. An increase of GAD(67)-IR somata was also found in the dentate gyrus and CA4. In anterograde tracer studies, amygdalo-hippocampal projection fibers were exclusively found in CA3 and CA2, but not CA1. Taken together, these results indicate that activation of amygdalo-hippocampal afferents is associated with the induction of significant changes in the GABA system of the hippocampus, with a subregional distribution that is remarkably similar to that found in SZ. Under pathologic conditions, an excessive discharge of excitatory activity emanating from the amygdala could be capable of altering inhibitory modulation along the trisynaptic pathway. This mechanism may potentially contribute to disturbances of GABAergic function in the major psychoses. Such "partial" rodent modelling provides an important strategy for deciphering the effect of altered cortico-limbic circuits in SZ.

Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology.

A variety of observations have suggested that the dopamine and serotonin systems may play a role in the pathophysiology and treatment of major mental disorders of childhood, adolescence and early adulthood. A recent triple immunofluorescence study has demonstrated a convergence of serotonin and dopamine fibers onto both pyramidal cells and GABAergic interneurons in the rat medial prefrontal cortex (mPFCx). These findings are consistent with the results of an electrophysiological study conducted in another laboratory that suggested such a relationship exists in the pyriform cortex of the rodent brain. During postnatal development, the dopamine system shows a progressive ingrowth of fibers into this region that continues until the early adult period. In contrast, GABAergic neurons appear to complete their postnatal maturation by the fourth postnatal week (the early post-weanling period). As dopamine fibers infiltrate the rat mPFCx, they progressively increase their interaction with neural elements within the neuropil and with the cell bodies of both pyramidal cells and GABAergic interneurons. This process appears to be influenced by the serotonin system, since lesioning of the nucleus raphe dorsalis during the neonatal period results in a significant increase of dopamine fibers. This finding suggests that lesions of the serotonin system induce plasticity of the cortical dopamine system; however, it is not known whether this inferred suppressive effect of serotonin fibers occurs at brainstem levels or within the mPFCx itself. Taken together, these various studies suggest that the convergence of dopamine and serotonin fiber systems on intrinsic cortical neurons shows considerable plasticity during postnatal life that could theoretically contribute to the development of 'miswired' circuits in individuals with neuropsychiatric disorders.

Amygdalo-entorhinal inputs to the hippocampal formation in relation to schizophrenia.

This chapter reviews recent postmortem studies of schizophrenic brain and discusses the potential role of the amygdala in the induction of hippocampal abnormalities in this disorder. Based on available evidence, sectors CA4, CA3, and CA2, but not CA1, show preferential changes in schizophrenic subjects, although the most pronounced changes have been found in CA3 and CA2. It seems likely that the amygdala would contribute in some way to the induction of abnormalities along the trisynaptic pathway via its direct input to sectors CA3 and CA2, as well as an indirect one that involves the entorhinal cortex and its perforant path projection to the area dentata. The postmortem findings reported to date have been integrated into a working model in which decreases of inhibitory GABAergic modulation are invoked to explain the observation from a recent PET scan study (Heckers et al., 1999) that baseline metabolic activity in the hippocampus of schizophrenics is increased. In addition, however, the apparent inability of schizophrenics to increase metabolic activity in the hippocampus when challenged with a memory retrieval task may reflect a disturbance of disinhibitory modulation postulated herein to occur in sector CA3, a key relay point along the trisynaptic pathway. Overall, it seems plausible that an increase of excitatory activity entering the hippocampus from the basolateral complex via both direct and indirect pathways may make a significant contribution to the pathophysiology of schizophrenia.

Emerging principles of altered neural circuitry in schizophrenia.

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

Acute administration of SCH23390 increases D(1) receptors on nonpyramidal neurons in rat mPFC.

Atypical antipsychotic drugs (APDs) such as clozapine and olanzapine antagonize both D(1) and D(2) receptors; however, little is known regarding their pharmacologic effect on specific neuronal elements within the local circuitry of corticolimbic regions, such as medial prefrontal cortex (mPFC). To characterize the effect of short-term antagonism of the D(1) receptor a high-resolution autoradiographic technique was used to assess the density (B(max)) and affinity (K(d)) of this receptor on pyramidal cells (i.e., large neurons (LNs, >/=100 microm(2))), nonpyramidal cells (i.e., small neurons (SNs, <100 microm(2))) and in the surrounding neuropil (NPL) of layer VI in rat mPFC. Either normal saline or the selective D(1) antagonist SCH23390 (1.0 mg/kg/day) were administered for 48 h via Alzet osmotic pumps. Frozen sections were incubated in [(3)H]SCH23390 (1-8 nM) in the presence or absence of the competitive inhibitor SKF38393 (10 microM). A microscopic adaptation to Scatchard analysis revealed a significant increase (82%) in B(max) for neuronal cell bodies (P < 0.05), but not for neuropil of drug-treated animals. Further analysis indicated that the increase in B(max) was present on SNs (94%, P < 0.05), but not LNs in SCH23390-treated rats. In contrast, K(d) values for LNs, SNs, and NPL were not significantly altered by drug treatment. Since the vast majority of SNs are nonpyramidal in nature, short-term administration of a selective D(1) antagonist seems to be associated with a preferential upregulation of this receptor on interneurons. Overall, these results are consistent with the hypothesis that the mechanism of action of atypical antipsychotic medications involves changes in D(1) receptor activity associated with local circuit neurons in rat mPFC.

Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain.

Recent postmortem studies have been suggesting that a defect of GABAergic neurotransmission might occur in the corticolimbic system of subjects with schizophrenia and bipolar disorder. To explore this possibility, a method for immunolocalizing the 65 kdalton isoform of glutamate decarboxylase (GAD(65)) has been developed and applied to the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of 12 normal controls (CONs), 12 schizophrenics (SZs) and 5 manic depressive (MDs) subjects. A computer-assisted technique was employed under strictly blind conditions to determine the density of GAD(65)-IR terminals in apposition with pyramidal (PNs) and nonpyramidal (NPs) neurons and in neuropil (NPL) of layers II, III, V and VI of each cortical region. For SZs, no difference in the numerical density of GAD(65)-IR terminals in contact with either PNs or NPs or in NPL of layers II-VI in ACCx or PFCx was detected. There were also no differences in the size of either PNs and NPs that could have influenced the nature of these findings. Using a pixel count analysis, the size of IR terminals was, however, found to be increased in layers II (10.3%) and III (15.8%) of SZs, but only in subjects treated with neuroleptic drugs. For MDs, the density of GAD(65)-IR terminals was significantly reduced in all four layers of ACCx, but these differences were most significant in layers II (27.8%) and III (37.2%), whether or not the subjected were treated with neuroleptics. In PFCx, the MDs showed similar differences in terminal density for PNs and NPs but not neuropil in the four laminae examined. The MD group showed no differences in either the size of cell bodies or IR terminals. Age and PMI did not account for any of the differences between the CONs vs SZs and MDs. Overall, the results of this study, though preliminary, suggest that there may be complex changes in GABAergic terminals in SZ and MD, ones that may vary with respect to primary diagnosis and neuroleptic exposure.

Localization of cells preferentially expressing GAD(67) with negligible GAD(65) transcripts in the rat hippocampus. A double in situ hybridization study.

Two major forms of glutamic acid decarboxylase (GAD) are present in the mammalian brain, a 65-kDa isoform (GAD(65)) and a 67-kDa isoform (GAD(67)), and it is usually assumed that all GABAergic neurons contain both. The two forms have not yet been colocalized to the same neurons, because the GAD(65) protein is found almost exclusively in axon terminals, while GAD(67) is found predominantly in the cell body. Using double in situ hybridization (DISH) with both radioactive [35S] and non-radioactive (digoxigenin, DIG) probes, the distributions of GAD(65) and GAD(67) mRNA have been simultaneously examined in the rat hippocampus. The results suggest that [35S] radioprobes are slightly more sensitive than DIG probes, and that the reversal of labels is necessary in DISH studies to determine whether a neuronal subtype which expresses only one isoform of GAD may be present. The data indicate that the majority of cells (90%) showing labeling were labeled for both GAD(65) and GAD(67) mRNA. In sectors CA1 and CA3 approximately 5-10% of the cells positive for GAD(67) showed little or no detectable GAD(65) mRNA. In the hilus, however, GAD(65) levels were higher, and all cells seem to express both GAD(65) and GAD(67) mRNA. Taken together, these results support the view that most GABAergic neurons in the hippocampus express both GAD(65) and GAD(67). However, it appears that some interneurons in the CA subfields differ from "classic" GABAergic interneurons by preferentially expressing the 67-kDa isoform of GAD under baseline conditions, with GAD(65) mRNA levels very low or absent.

Evidence for altered trisynaptic circuitry in schizophrenic hippocampus.

Recent postmortem studies have demonstrated subtle alterations in the hippocampal formation (HIPP) of patients with schizophrenia (SZ). These changes include a decreased density of nonpyramidal neurons (NPs), an increase of the GABAA, but not benzodiazepine receptors and a neuroleptic-dose-related increase of GAD65-IR terminals, particularly in sectors CA3 and CA2. High resolution studies of the GABAA receptor have further suggested that a decrease of disinhibitory GABAergic activity (i.e., GABA-to-GABA) in stratum pyramidale of CA3 may coexist with reduced inhibitory modulation (i.e., GABA-to-excitatory pyramidal neuron) in the stratum oriens of this same sector. These changes could potentially involve excitotoxic damage to interneurons in CA2; but, the precise time frame for the induction of such an injury during pre- versus postnatal life cannot as yet be inferred from the available data. These findings are consistent with reports of abnormal oscillatory rhythms and increased basal metabolic activity in the HIPP of patients with SZ. The fact that patients with manic depression also show a decrease of NPs in CA2 suggests that changes in the GABA system may not be related to a susceptibility gene for SZ. Rather, these alterations could be associated with a nonspecific factor, such as stress, experienced either early in life or much later during adolescence or adulthood. Presumably, there are also changes associated in other transmitter systems that may play a more specific role in establishing the SZ phenotype.

Effect of age and neuroleptics on tyrosine hydroxylase-IR in sector CA2 of schizophrenic brain.

The density of TH-IR varicosities was analyzed in the hippocampus of 15 normal controls and 11 schizophrenics. The average density of varicosities in apposition with pyramidal cells and in the neuropil was 30-35% lower in CA2, but not other sectors of schizophrenics. Age was correlated with varicosity density in all sectors, particularly in CA2 where young patients showed a 50% reduction on non-pyramidal cells. Neuroleptic dose showed a negative correlation with the density of varicosities, and notably the dose of young schizophrenics was four times higher than that of older subjects. Thus, antipsychotic dose appears to be associated with a suppression of a normal age-related increase of dopamine projections to CA2 during the early phases of schizophrenia.