Apoptosis in GABA Cells in Hippocampal Circuitry

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We have developed a rodent model for neural circuitry changes in postmortem studies of the limbic lobe in schizophrenia (SZ). Based on observations that there is a preponderance of abnormalities in layer II of anterior cingulate cortex and sectors CA3/2 of hippocampus (HIPP) in SZs and both these sites receive an abundant projection from the basolateral amygdala (BLn), we have postulated that this nucleus may play a role in the induction of abnormalities in ACCx-ll and CA3/2 of SZs and bipolars (BDs). By stereotaxically infusing the non-competitive GABAA antagonist, picrotoxin (PICRO), into the basolateral amygdala (BLn), we have observed changes in GABAergic neurons in the HIPP remarkably similar to those seen in SZ. These studies have demonstrated that acute administration of PICRO results in complex changes of various subtypes of GABAergic neurons, particularly those in sectors CA3/2. Using gene expression profiling (GEP), we have reported that PICRO-treated rats show significant changes in several biologically relevant clusters of genes that include monoamine and peptide G-coupled protein (GPCRs) and apoptosis, that overlap with those showing changes in SZ and BD. In addition, to increased expression of the D4 receptor, as well as pro-apoptotic changes in BAX, c-myc and Bcl-2, we have also observed changes in the regulation of the L-Type calcium channel-ID (L-VGCC-1D) in both postmortem studies and in the rodent model. These genes show changes in expression not only in the HIPP of rats receiving acute or chronic infusion of PICRO on the BLn, but also in the HIPP of SZs and BDs. This overlap in gene expression profiling data across rat and human studies suggests that this model is a) valid, b) the data obtained are reliable, and c) those observed in humans may be related to the activation of the amygdalo-HIPP pathway that occurs in relation to environmental stress. In addition to the above target genes, we will also study the expression of subunits associated with NMDA (NR2A), AMPA (GluR1) and kainite (GluR6) receptors, since many postmortem studies have demonstrated evidence of a down-regulation of these glutamate receptors in SZ and excitotoxicity has been implicated in neuronal dysfunction in both SZ and BD. The subunits chosen show decreased expression in the chronic PICRO model and in patients with psychotic disorders. In the proposed experiments, a chronic infusion paradigm (4 wks continuous infusion of PICRO) will be used together with systemic administration of corticosterone (CORT) to simulate the conditions that might occur in the HIPP in response to environmental stress. We will test the hypothesis that amygdalar activation of the HIPP results in apoptotic changes in GABA cells, ones that are mediated via glutamate receptors and calcium channel activity.