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

Abstract

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-beta and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1beta, (GRIK2/3), TGF-beta2, TGF-betaR1, histone deacetylase 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-beta 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.

Fig. 1.

Schematic diagram based on ingenuity association analysis depicting the respective changes in the GAD₆₇ regulatory network shown in Fig. 2 of SZs vs. BDs. The kainate receptors, which are up- and down-regulated, respectively, in SZ and BDs, are depicted as playing a central role in mediating the effect of basolateral amygdalar afferents on GABA cells in the SO of CA2/3. Cyclin D2 may be a pivotal gene that interfaces this network with that for cell cycle regulation.

Fig. 2.

QRT-PCR validation of microarray-based GEP data. The results for GAD₆₇, HDAC1, LEF1, Runx2, PAX5, and GRIK1/3 show changes in the same direction as those observed with microarray. The error bars are very small; however, the P value of 0.001 is robust for the REST analysis that was used. The error bars for GAD₆₇ appear to be larger than those of the other genes because of the proportions of the graph needed to accommodate the data for all of the genes. On a percent basis, the error bars for GAD₆₇ when expressed as a percent of the mean are relatively similar to those for the other genes.