We have developed a rodent model for neural circuitry changes in postmortem studies of the limbic lobe inschizophrenia (SZ). Based on observations that there is a preponderance of abnormalities in layer II ofanterior cingulate cortex and sectors CA3/2 of hippocampus (HIPP) in SZs and both these sites receive anabundant projection from the basolateral amygdala (BLn), we have postulated that this nucleus may play arole in the induction of abnormalities in ACCx-ll and CA3/2 of SZs and bipolars (BDs). By stereotaxicallyinfusing 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 varioussubtypes 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 clustersof genes that include monoamine and peptide G-coupled protein (GPCRs) and apoptosis, that overlap withthose showing changes in SZ and BD. In addition, to increased expression of the D4 receptor, as well aspro-apoptotic changes in BAX, c-myc and Bcl-2, we have also observed changes in the regulation of the L-Typecalcium channel-ID (L-VGCC-1D) in both postmortem studies and in the rodent model. These genesshow changes in expression not only in the HIPP of rats receiving acute or chronic infusion of PICRO on theBLn, but also in the HIPP of SZs and BDs. This overlap in gene expression profiling data across rat andhuman studies suggests that this model is a) valid, b) the data obtained are reliable, and c) those observedin humans may be related to the activation of the amygdalo-HIPP pathway that occurs in relation toenvironmental stress. In addition to the above target genes, we will also study the expression of subunitsassociated with NMDA (NR2A), AMPA (GluR1) and kainite (GluR6) receptors, since many postmortemstudies have demonstrated evidence of a down-regulation of these glutamate receptors in SZ andexcitotoxicity has been implicated in neuronal dysfunction in both SZ and BD. The subunits chosen showdecreased expression in the chronic PICRO model and in patients with psychotic disorders. In the proposedexperiments, a chronic infusion paradigm (4 wks continuous infusion of PICRO) will be used together withsystemic administration of corticosterone (CORT) to simulate the conditions that might occur in the HIPP inresponse to environmental stress. We will test the hypothesis that amygdalar activation of the HIPP results inapoptotic changes in GABA cells, ones that are mediated via glutamate receptors and calcium channelactivity.
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