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 Ill 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.
|Subburaju, S; Coleman, A J; Ruzicka, W B et al. (2016) Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model. Transl Psychiatry 6:e723|
|Ohtsuka, Nobuhisa; Badurek, Sylvia; Busslinger, Meinrad et al. (2013) GABAergic neurons regulate lateral ventricular development via transcription factor Pax5. Genesis 51:234-45|
|Subburaju, Sivan; Benes, Francine M (2012) Induction of the GABA cell phenotype: an in vitro model for studying neurodevelopmental disorders. PLoS One 7:e33352|
|Sheng, Guoqing; Demers, Matthew; Subburaju, Sivan et al. (2012) Differences in the circuitry-based association of copy numbers and gene expression between the hippocampi of patients with schizophrenia and the hippocampi of patients with bipolar disorder. Arch Gen Psychiatry 69:550-61|
|Benes, Francine M (2012) Nicotinic receptors and functional regulation of GABA cell microcircuitry in bipolar disorder and schizophrenia. Handb Exp Pharmacol :401-17|
|Gisabella, Barbara; Bolshakov, Vadim Y; Benes, Francine M (2012) Kainate receptor-mediated modulation of hippocampal fast spiking interneurons in a rat model of schizophrenia. PLoS One 7:e32483|
|Gisabella, Barbara; Cunningham, Miles G; Bolshakov, Vadim Y et al. (2009) Amygdala-dependent regulation of electrical properties of hippocampal interneurons in a model of schizophrenia. Biol Psychiatry 65:464-72|
|Benes, Francine M; Lim, Benjamin; Subburaju, Sivan (2009) Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars. Proc Natl Acad Sci U S A 106:11731-6|
|Lisman, John E; Coyle, Joseph T; Green, Robert W et al. (2008) Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 31:234-42|
|Woo, Tsung-Ung W; Shrestha, Kevin; Lamb, Dorian et al. (2008) N-methyl-D-aspartate receptor and calbindin-containing neurons in the anterior cingulate cortex in schizophrenia and bipolar disorder. Biol Psychiatry 64:803-9|
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