| 1 | Proc。纳特。学院科学。美国2007年6月104日：10164-9 |
|---|---|
| PMID | 17553960 |
| Title | 精神分裂症和双曲片海马中GABA细胞表型的调节。 |
| Abstract | GABAergic dysfunction is present in the hippocampus in精神分裂症（SZ）和躁郁症（BD）。将三突触途径“解构”成CA3/2和CA1的各个层以及进行的基因表达分析。网络关联分析用于发现可能与谷氨酸脱羧酶67（GAD（67））调节有关的基因，该系统的标记已被许多研究发现显示出在SZS和BDS中的表达降低。最引人注目的变化是两组Ca2/3层中GAD（67）的下调；CA1仅显示SO的变化精神分裂症s。GAD生成的网络（67）包含25个基因，其中涉及海谷酸酯受体，TGF-β和WNT信号传导，以及涉及细胞生长和分化的转录因子。在SZS中，IL-1Beta（Grik2/3），TGF-BETA2，TGF-BETAR1，组蛋白脱乙酰基酶1（HDAC1），死亡相关蛋白（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. |
| SCZ Keywords | 精神分裂症, schizophrenics |
| 2 | Proc。纳特。学院科学。美国2007年6月104日：10164-9 |
| PMID | 17553960 |
| Title | 精神分裂症和双曲片海马中GABA细胞表型的调节。 |
| Abstract | GABAergic dysfunction is present in the hippocampus in精神分裂症（SZ）和躁郁症（BD）。将三突触途径“解构”成CA3/2和CA1的各个层以及进行的基因表达分析。网络关联分析用于发现可能与谷氨酸脱羧酶67（GAD（67））调节有关的基因，该系统的标记已被许多研究发现显示出在SZS和BDS中的表达降低。最引人注目的变化是两组Ca2/3层中GAD（67）的下调；CA1仅显示SO的变化精神分裂症s。GAD生成的网络（67）包含25个基因，其中涉及海谷酸酯受体，TGF-β和WNT信号传导，以及涉及细胞生长和分化的转录因子。在SZS中，IL-1Beta（Grik2/3），TGF-BETA2，TGF-BETAR1，组蛋白脱乙酰基酶1（HDAC1），死亡相关蛋白（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. |
| SCZ Keywords | 精神分裂症, schizophrenics |
| 3 | PLoS ONE 2012 -1 7: e33352 |
| PMID | 22457755 |
| Title | GABA细胞表型的诱导：研究神经发育障碍的体外模型。 |
| Abstract | 关于海马的最新研究表明，基因网络与GAD的调节有关？（GAD1）表达并可能在？ - 氨基丁酸（GABA）功能障碍中起作用精神分裂症（SZ）和躁郁症（BD）。要获得对GAD的更详细的了解？调控可能导致GABA能功能障碍，我们开发了一个体外模型，其中GABA细胞与海马前体前体细胞系HIB5区分开。PDGF和BDNF等生长因子通过诱导GAD的表达来调节GABA表型？并刺激细胞过程的生长，许多带有生长锥的生长锥与其他GAD阳性细胞的细胞体和过程形成。这些变化与乙酰化微管蛋白，微管相关蛋白2（MAP2）和突触后密度蛋白95（PSD95）的表达增加有关。添加BDNF与PDGF一起增加了GAD ??的mRNA和蛋白质水平，以及高亲和力GABA摄取蛋白GAT1。这些变化与“分化” Hib5神经元细胞质中GABA浓度的增加有关。在面前？和K？，新合成的GABA被细胞外释放。 When the HiB5 cells appear to be fully differentiated, they also express GAD??, parvalbumin and calbindin, and GluR subtypes as well as HDAC1,daxx，pax5，runx2，与gad关联??规定。总体而言，这些结果表明，在存在与GAD相关的基因产物的存在下，HIB5细胞可以分化为功能成熟的GABA神经元？成人海马的调节。 |
| SCZ Keywords | 精神分裂症, schizophrenics |
| 4 | JAMA精神病学2015年6月72日：541-51 |
| PMID | 25738424 |
| Title | Circuit- and Diagnosis-Specific DNA Methylation Changes at ?-Aminobutyric Acid-Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder. |
| Abstract | 功能障碍相关?酸氨基丁酸(GABA)ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression. Several genes within this GAD1 regulatory network show diagnosis- and sector-specific expression changes within the circuitry of the hippocampus, influencing abnormal GAD1 expression in精神分裂症and bipolar disorder. 为了研究假说，即异常DNA甲基化有助于精神病中GAD1调节网络基因的电路和诊断异常表达。 This epigenetic association study targeting GAD1 regulatory network genes was conducted between July 1, 2012, and June 30, 2014. Postmortem human hippocampus tissue samples were obtained from 8 patients with精神分裂症, 8 patients with bipolar disorder, and 8 healthy control participants matched for age, sex, postmortem interval, and other potential confounds from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts. We extracted DNA from laser-microdissected stratum oriens tissue of cornu ammonis 2/3 (CA2/3) and CA1 postmortem human hippocampus, bisulfite modified it, and assessed it with the Infinium HumanMethylation450 BeadChip (Illumina, Inc). The subset of CpG loci associated with GAD1 regulatory network genes was analyzed in R version 3.1.0 software (R Foundation) using the minfi package. Findings were validated using bisulfite pyrosequencing. 1308 GAD1调节网络相关的CpG基因座的甲基化水平既作为单个位点，以识别差异化甲基化位置，并通过在共定位探针之间共享信息以鉴定差异化甲基化区域。 在所有6组中（3个诊断类别中的每个2个电路位置）和54个用P差异甲基化区域鉴定了146个差异检测率低于0.05的差异甲基化位置。daxxat specific loci within the hippocampus of patients with精神分裂症and bipolar disorder. This work demonstrates diagnosis- and circuit-specific DNA methylation changes at a subset of GAD1 regulatory network genes in the human hippocampus in精神分裂症and bipolar disorder. These genes participate in chromatin regulation and cell cycle control, supporting the concept that the established GABAergic dysfunction in these disorders is related to disruption of GABAergic interneuron physiology at specific circuit locations within the human hippocampus. |
| SCZ Keywords | 精神分裂症, schizophrenics |
| 5 | Transl Psychiatry 2016 -1 6: e723 |
| PMID | 26812044 |
| Title | Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model. |
| Abstract | 精神分裂症(SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 anddaxx。为了表征这些因素对假设SZ基础的发育扰动的贡献，携带短发夹RNA干扰（SHRNAI）的慢病毒载体和HDAC1和daxx被使用。在海马GABA神经元培养模型中，HIB5用HDAC1 shRNAi转导的HIB5显示HDAC1 mRNA的抑制作用为40％，HDAC1蛋白抑制60％。GAD67是与GABA合成相关的一种酶，增加了两倍（mRNA）。该蛋白质显示出35％。表达daxx, a co-repressor of HDAC1, was not influenced by HDAC1 inhibition. Transduction of HiB5 cells withdaxxshRNAi resulted in a 30% inhibition ofdaxxmRNA that translated into a 90% inhibition ofdaxxprotein. GAD1 mRNA was upregulated fourfold, while its protein increased by ~30%. HDAC1 expression was not altered by inhibition ofdaxx。但是，HDAC1和daxxwas demonstrated by co-immunoprecipitation. Inhibition of HDAC1 ordaxxEGR-1的表达增加，以前已证明调节GAD67启动子的转录因子。我们的体外结果表明HDAC1和daxxin the regulation of GAD67 in GABAergic HiB5 cells, strongly suggesting that these epigenetic/transcription factors contribute to mechanisms underlying GABA cell dysfunction in SZ. |
| SCZ Keywords | 精神分裂症, schizophrenics |