This is a resubmission of a competitive renewal application (ROl MH42261-14) for postmortem studies of the limbic lobe in relation to schizophrenia (SZ) and bipolar disorder (BD). Recent work from this laboratory has demonstrated a series of microscopic anomalies in layer II of the anterior cingulate cortex (ACCx-ll) and sectors CA3 and CA2 of the hippocampal formation (HIPP) in SZs and BDs. These changes have included reductions in interneurons, although an overt loss of GABA cells now appears to be a striking feature of GD, but not SZ. Even so, both SZs and BDs show evidence for a decrease of GABAergic function in ACCx-ll and HIPP.
Specific Aim I will test the hypothesis that discrepancies in cell counting data in ACCx and HIPP of SZs and/or BDs can be explained in part by differences in sampling window size employed in 2D vs 3D counting.
Specific Aim II will test the hypothesis that there will be a reduction in cells positive for GAD in HIPP sectors CA3 and CA2, as well as layers II and Ill of ACCx in BDs, but not SZs or their family members. In addition, it is also postulated that dopaminergic inputs to GABA cells are in increased in ACCx-ll of SZs, but not BDs.
Specific Aim I ll will test the hypothesis that in ACCx and HIPP of SZs and their first degree relatives there will be a decrease of the kainate receptor in PNs, while the NMDA receptor will be decreased in NPs.
Specific Aim I V will test the hypothesis that neurons in SZs will show less evidence of apoptosis than patients with BD and this will be especially apparent in interneurons. Taken together, the proposed studies are seeking to identify specific aspects of limbic circuitry that may be involved in the induction of neuronal pathology in SZ and BD. By learning more about the possible role of oxidative stress, novel forms of pharmacotherapy for the major neuropsychiatric disorders may eventually be developed.
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