Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars

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作者：

FM Benes，B Lim，D Matzilevich，JP Walsh，S Subburaju，M Minns

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摘要：

GABAergic dysfunction is present in the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). The trisynaptic pathway was "deconstructed" into various layers of sectors CA3/2 and CA1 and gene expression profiling performed. Network association analysis was used to uncover genes that may be related to regulation of glutamate decarboxylase 67 (GAD_(67)), a marker for this system that has been found by many studies to show decreased expression in SZs and BDs. The most striking change was a down-regulation of GAD_(67) in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD_(67) contained 25 genes involved in the regulation of kainate receptors, TGF-β and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, 1L-1β, (GRIK2/3), TGF-β2, TGF-βR1, histone deacety-lase 1 (HDAC1), death associated protein (DAXX), and cyclin D2 (CCND2) were all significantly up-regulated, whereas in BDs, PAX5, Runx2, LEF1, TLE1, and CCND2 were significantly down-regulated. In the SO of CA1 of BDs, where GAD67 showed no expression change, TGF-β and Wnt signaling genes were all up-regulated, but other transcription factors showed no change in expression. In other layers/sectors, BDs showed no expression changes in these GAD_(67) network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD_(67) may be associated with an epigenetic mechanism in SZ. In BD, however, a suppression of transcription factors involved in cell differentiation may contribute to GABA dysfunction.

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关键词：

epigenetics network association analysis PAX5 Runx2 HDAC1

DOI：

10.1073/pnas.0703806104

被引量：

670

年份：

2007