Mouse models for GABA epigenetic dysfunction

描述(由申请人提供)：发现精神分裂症(SZ)是一种以Reelin和GAD67减少为特征的疾病(Guidotti等人，2000)，皮质GABA能中间神经元DNMT1 mRNA的表达增加(Costa等人，2002a)，以及Reelin启动子CpG岛的高甲基化(Grayson，Personal Communication)促使我们考虑启动子CpG岛的高甲基化是导致SZ中GABA能神经元功能障碍的一个机制。该项目的首要目标是建立表观遗传的reelin和GAD67表达下调的动物模型。我们推测，长期给予L蛋氨酸，可在小鼠端脑GABA能神经元中复制下调SZ脑皮质GABA能神经元中Reelin和GAD67的表达，剂量增加：i)甲基供体S-腺苷-蛋氨酸的含量；ii)dna-(胞嘧啶-5)-甲基转移酶(DNMT1)活性；iii)reelin和Gade？富含CpG的启动子区域5位甲基化的共价胞嘧啶残基。基因。 DNMT1调控基因活性的调控机制之一是它对靶DNA片段的可及性。这种可及性可能由核小体核心组蛋白的乙酰化或去乙酰化状态调节，核小体核心组蛋白由组蛋白乙酰转移酶(HAT)和组蛋白脱乙酰酶(HDAC)的活性平衡控制。癌症领域的研究表明，在肿瘤细胞中观察到的DNMT活性的增加可以通过使用特定的抑制剂降低HDAC活性来下调。因此，我们将注意力集中在HDAC抑制剂(即丙戊酸盐和苯甲酰胺)作为可能的药物的作用上，这些药物可能通过增加核小体上核心组蛋白尾部的乙酰化，使端脑GABA能神经元的细胞核正常化-由reelin或GAD67启动子CpG岛的高甲基化诱导的reelin和GAD67表达下调。 最近的报告表明，典型和非典型抗精神病药物如果与丙戊酸盐(VPA)联合使用，会更有效、更有效、毒性更低。使用弱的HDAC抑制剂VPA治疗SZ的有益效果表明，更有效的HDAC抑制剂可能代表着一个新的机会，可以进行具有潜在治疗价值的药物干预，以减轻高危个体对SZ的易感性。

DESCRIPTION (provided by applicant): The finding that schizophrenia (SZ) is a disorder characterized by a decrease of reelin and GAD67 (Guidotti et al., 2000), an increase of DNMT1 mRNA expression in cortical GABAergic interneurons (Costa et al., 2002a), and a hypermethylation of the reelin promoter CpG islands (Grayson, personal communication) encouraged us to consider that hypermethylation of promoter CpG islands is a mechanism operative in the dysfunction of GABAergic neurons in SZ. This project's overarching objective is to develop animal models of epigenetic reelin and GAD67 expression downregulation. We hypothesize that the downregulation of reelin and GAD67 in cortical GABAergic neurons of SZ brains can be replicated in mouse telencephalic GABAergic neurons with protracted administration of L-methionine in doses that increase: i) the content of the methyl donor S-adenosyl-methionine; ii) DNA-(cytosine-5)-methyltransferase (DNMT1) activity; and iii) covalent cytosine residues methylated in position 5 on the CpG-rich promoter regions of reelin and GADe? genes. One of the regulatory mechanisms involved in the process of control of gene activity by DNMT1 is its accessibility to target DNA segments. This accessibility may be regulated by the acetylated or deacetylated status of the nucleosomal core histones, which is governed by the balance of the activities of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Studies in the field of cancer suggest that the increased activity of DNMTs observed in tumor cells can be downregulated by reducing HDAC activities with specific inhibitors. Hence, we have focused our attention on the action of HDAC inhibitors (i.e., valproate and benzamides) as putative drugs that may, by increasing core histone tail acetylation at nucleosomal sites, normalize in nuclei of telencephalic GABAergic neurons-reelin and GAD67 expression downregulation induced by hypermethylation of reelin or GAD67 promoter CpG islands. Recent reports suggest that typical and atypical antipsychotics are more potent, more efficacious, and less toxic if they are co-administered with valproate (VPA). The beneficial effects in the treatment of SZ obtained with the weak HDAC inhibitor VPA suggest that more potent HDAC inhibitors may represent a new opportunity for pharmacological interventions of putative therapeutic value in mitigating vulnerability to SZ among high risk individuals.