Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars
Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars
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DOI：
10.1073/pnas.0703806104
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发表时间：
2007-06-12
影响因子：
11.1
通讯作者：
Minns, Martin
中科院分区：
文献类型：
--
作者：
Benes, Francine M.;Lim, Benjamin;Minns, Martin
精神分裂症 (SZ) 和双相情感障碍 (BD) 患者的海马体中存在 GABA 能功能障碍。三突触通路被“解构”为 CA3/2 和 CA1 部分的各个层，并进行基因表达谱分析。网络关联分析用于揭示可能与谷氨酸脱羧酶 67 (GAD(67)) 调节相关的基因，谷氨酸脱羧酶 67 (GAD(67)) 是该系统的一个标记，许多研究发现它在 SZ 和 BD 中表达降低。最显着的变化是两组 CA2/3 的定向层 (SO) 中 GAD67 的下调； CA1仅显示精神分裂症患者SO的变化。为 GAD67 生成的网络包含 25 个参与红藻氨酸受体调节、TGF-β 和 Wnt 信号传导以及参与细胞生长和分化的转录因子的基因。在 SZ 中，IL-1 ss (GRIK2/3)、TGF-ss 2、TGF-ss R1、组蛋白脱乙酰酶 1 (HDAC1)、死亡相关蛋白 (DAXX) 和细胞周期蛋白 D2 (CCND2) 均显着上调，而在 BD 中，PAX5、Runx2、LEF1、TLE1 和 CCND2 显着下调。在BDs CA1区SO中，GAD67表达无变化，TGF-P和Wnt信号基因均上调，但其他转录因子表达无变化。在其他层/扇区中，BD 显示这些 GAD67 网络基因的表达没有变化。总的来说，这些结果与 GAD67 表达减少可能与 SZ 的表观遗传机制有关的假设是一致的。然而，在 BD 中，参与细胞分化的转录因子的抑制可能导致 GABA 功能障碍。
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 GAD67 in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD67 contained 25 genes involved in the regulation of kainate receptors, TGF-ss and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1 ss, (GRIK2/3), TGF-ss 2, TGF-ss 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-P 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 GAD67 network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD67 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.