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-␤ and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1␤, (GRIK2/3), TGF-␤2, TGF-␤R1, 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-␤ 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.epigenetics ͉ network association analysis ͉ PAX5 ͉ Runx2 ͉ HDAC1

Significant reductions in GABAergic cell numbers and/or activity have been demonstrated in the hippocampus of subjects with schizophrenia and bipolar disorder. To understand how different subpopulations of interneurons are regulated, laser microdissection and gene expression profiling have been used to ''deconstruct'' the trisynaptic pathway, so that subtypes of GABA cells could be defined by their location in various layers of CA3/2 and CA1. The results suggest that the cellular endophenotypes for SZ and BD may be determined by multiple factors that include unique susceptibility genes for the respective disorders and altered integration among hippocampal GABA cells with extrinsic and intrinsic afferent fiber systems. The extensive and intricate data that has come from this study has provided insights into how a complex circuit, like the trisynaptic pathway, may be regulated in human hippocampus in both health and disease.GAD67 ͉ potassium ion transport ͉ synaptic transmission ͉ kainate ͉ nicotinic G ene expression plays a central role in the regulation of neural circuitry involved in cognitive behavior. Identifying molecular mechanisms within neurons of complex circuits presents one of the foremost challenges to understanding the human brain. In the past 20 years, postmortem studies of schizophrenia (SZ) and bipolar disorder (BD) have provided evidence for a dysfunction of GABAergic neurons in frontal cortices and hippocampus (1). It is well known that GABAergic interneurons provide potent inhibitory modulation of principle neurons (2) and are critical for the regulation of feed-forward inhibition (3) and oscillatory rhythms (4, 5). A network of genes involved in the regulation of glutamate decarboxylase 67 (GAD 67 ), a key marker for the GABA cell phenotype (6), shows changes in expression in SZ that are different from those seen in BD, suggesting that there may be unique molecular endophenotypes for each disorder. To learn more about the molecular regulation of hippocampal GABA cells in SZ and BD, a combination of laser microdissection (LMD) and gene expression profiling has been used to ''deconstruct'' the trisynaptic pathway into subtypes of GABA neurons defined by their location and connectivity. Several clusters of genes have been examined across a broad array of cellular functions that include transduction, signaling, metabolism, translation, transcription and cell cycle regulation. These clusters have been separately analyzed in various layers and sectors with a preponderance of GABA cells. To our knowledge, this is the first demonstration that the regulation of gene expression in GABA cells varies not only according to diagnosis, but also to location within a complex circuit.

GABA cell dysfunction in both schizophrenia (SZ) and bipolar disorder (BD) involves decreased GAD 67 expression, although this change involves fundamentally different networks of genes in the 2 disorders. One gene that is common to these 2 networks is cyclin D2, a key component of cell cycle regulation that shows increased expression in SZ, but decreased expression in BD. Because of the importance of cell cycle regulation in maintaining functional differentiation and DNA repair, the current study has examined the genes involved in the G 1 and G 2 checkpoints to generate new hypotheses regarding the regulation of the GABA cell phenotype in the hippocampus of SZ and BD. The results have demonstrated significant changes in cell cycle regulation in both SZ and BD and these changes include the transcriptional complex (TC) that controls the expression of E2F/DP-1 target genes critical for progression to G 2 /M. The methyl-CpG binding domain protein (MBD4) that is pivotal for DNA repair, is significantly up-regulated in the stratum oriens (SO) of CA3/2 and CA1 in SZs and BDs. However, other genes associated with the TC, and the G 1 and G 2 checkpoints, show complex changes in expression in the SO of CA3/2 and CA1 of both SZs and BDS. Overall, the patterns of expression observed have suggested that the regulation of functional differentiation and/or genomic integrity of hippocampal GABA cells varies according to diagnosis and their location within the trisynaptic pathway.

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