The studies described in this proposal are a logical follow-up to our earlier work showing subtle alterations of intrinsic neural circuitry in the hippocampus (HIPP) of schizophrenic (SZ) and bipolar disorder (BD) subjects. Some of these abnormalities have suggested that cellular and molecular changes in pathways associated with cell viability may lead to cell death in BDs and, to a lesser degree, SZs. We recently tested this hypothesis using gene expression profiling (GEP), together with a novel post hoc analysis of GenMapp biopathways/clusters. A pronounced upregulation of genes associated with calcium channels, monoamine and peptide G-coupled protein receptors (GPCRs) and multiple signaling pathways including apoptosis, TFG-p and Wnt has been observed in BDs. In SZs, these same pathways are affected, but in the opposite direction, suggesting that at least some of these changes may be related to susceptibility genes for each of the disorders. To learn more about cellular regulatory mechanisms in the HIPP of BDs and SZs, we are proposing to use two cohorts, one composed of a well-characterized set of normal controls, SZs and BDs called the McLean 66 and another consisting of first degree relatives of SZs (SZ-F) and matched controls.
In Specific Aim I, a combination of GEP, laser capture microdissection (LCM) and quantitative RT-PCR will be used to determine whether these changes are present in particular subregions, sublaminae and cellular subtypes in sectors CA3/2 versus CA1 in HIPP of BDs and SZs. In later studies, we will perform GEP in the SZ-F cohort to determine whether there are similarities in the expression profiles in SZs. In addition, data from our 'partial'rodent model of SZ in which picrotoxin is acutely and chronically infused in the amygdala will also be used to evaluate whether genes showing overlapping changes in BDs, SZs and PICRO-treated rats may be related to amygdalar activation of the HIPP.
In Specific Aim II, we will validate and extend the GEP results by using double in situ hybridization (DISH) to co-localize mRNA from several target genes associated with apoptosis and other GenMapp pathways/clusters with GAD65 mRNA to determine whether key changes are preferentially occurring in GABAergic or non-GABAergic neurons. Overall, the proposed studies are seeking to replicate, validate and extend our GEP studies in critical ways that will provide a more detailed understanding of where pivotal changes in gene expression may be occurring within discrete aspects of HIPP circuitry and whether such changes may be related to genetic or environmental factors associated with the psychotic disorders.
|Ruzicka, W Brad; Subburaju, Sivan; Coyle, Joseph T et al. (2018) Location matters: distinct DNA methylation patterns in GABAergic interneuronal populations from separate microcircuits within the human hippocampus. Hum Mol Genet 27:254-265|
|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|
|Ruzicka, W Brad; Subburaju, Sivan; Benes, Francine M (2015) Circuit- and Diagnosis-Specific DNA Methylation Changes at ?-Aminobutyric Acid-Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder. JAMA Psychiatry 72:541-51|
|Benes, Francine M (2015) Building models for postmortem abnormalities in hippocampus of schizophrenics. Schizophr Res 167:73-83|
|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|
|Benes, Francine M (2011) Regulation of cell cycle and DNA repair in post-mitotic GABA neurons in psychotic disorders. Neuropharmacology 60:1232-42|
|Benes, Francine M (2010) Relationship of GAD(67) regulation to cell cycle and DNA repair in GABA neurons in the adult hippocampus: bipolar disorder versus schizophrenia. Cell Cycle 9:625-7|
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