GABAergic molecular pathology in schizophrenia

精神分裂症的 GABA 分子病理学

• 批准号: 6918287
• 负责人: ERMINIO COSTA
• 金额: $ 31万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-21 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918287
• 关键词: CpG islands; DNA methylation; S adenosylmethionine; acyltransferase; amidohydrolases; bipolar depression; caudate nucleus; enzyme induction /repression; gamma aminobutyrate; gene expression; genetic promoter element; genetic regulation; glutamate decarboxylase; histones; human tissue; interneurons; major depression; methyltransferase; molecular pathology; neural cell adhesion molecules; neuropathology; occipital lobe /cortex; polymerase chain reaction; prefrontal lobe /cortex; pyramidal cells; schizophrenia; tissue /cell culture; valproate

DESCRIPTION (provided by applicant): Prefrontal cortex (RFC) GABAergic interneurons are a major target for the molecular pathology associated with schizophrenia (SZ) morbidity; their alteration may contribute to the reduction of cortical neuropil, which is an important component of SZ pathophysiology. Cortical GABAergic neurons participate in the orchestration of cortical pyramidal neuron population firing via the release of GABA on GABAA and GABAB receptors and modulate dendritic spine plasticity via the translation of spine resident mRNAs facilitated by the GABAergic neuron release of reelin acting on integrin receptors located on dendritic spine postsynaptic densities. In SZ cortical GABAergic neurons, the synthesis of GABA and reelin is reduced because of a downregulation in GAQ67 and reelin mRNA expressions. Very probably this is due to an increased expression in GABAergic neurons of DNA-(cytosine 5)-methyltransferase1 (DNMT1) that contributes to the epigenetic hypermethylation of CpG islands and promoters expressed in reelin and GAD67 genes and to the consequent decreased synthesis of these two gene transcripts. Thus, we hypothesize that downregulation of GABAergic function due to an epigenetic mechanism may be an important primary process operative in SZ morbidity. We will study whether: 1) in addition to BA9 and BA10 GABAergic neurons, DNMT1 is coexpressed with reelin and GAD67, in the GABAergic neurons of the occipital cortex and caudate nucleus; 2) in every GABAergic neuron, the increase of DNMT1 expression coincides with a decrease of reelin and GAD67 expression; 3) the increase of DNMT1 and the decrease of reelin and GAD67 expression also extend to brains of bipolar disorder patients; 4) DNMT1 establishes a partnership with complexes including histone deacetylases and histone methylases, two prominent enzymes to regulate the code whereby histones control accessibility of transcription factors or DNMT1 to targeted regulatory sites in gene promoters. A better understanding of how epigenetic mechanisms can regulate reelin and GAD67 gene transcription may allow the discovery of new drug targets that can reprogram transcription and perhaps modify pathologies related to epigenetically-induced downregulation of gene expression in SZ.

描述（由申请人提供）：前额皮质（RFC） gaba能中间神经元是与精神分裂症（SZ）发病率相关的分子病理学的主要靶点；它们的改变可能导致皮质神经pil的减少，这是SZ病理生理的重要组成部分。皮质GABA能神经元通过释放GABAA和GABAB受体上的GABA，参与皮质锥体神经元群放电的协调，并通过翻译脊柱驻留mrna来调节树突脊柱的可塑性，而GABA能神经元释放的reelin作用于树突脊柱突触后密度的整合素受体，从而促进脊柱驻留mrna的翻译。在SZ皮质GABA能神经元中，由于GAQ67和reelin mRNA表达下调，GABA和reelin的合成减少。这很可能是由于gaba能神经元中DNA-（胞嘧啶5）-甲基转移酶1 （DNMT1）的表达增加，导致表观遗传的CpG岛和reelin和GAD67基因中表达的启动子高甲基化，从而导致这两个基因转录物的合成减少。因此，我们假设由于表观遗传机制导致的gaba能功能下调可能是SZ发病的一个重要的主要过程。我们将研究：1)除BA9和BA10 gab能神经元外，DNMT1是否与reelin和GAD67在枕皮质和尾状核gab能神经元中共表达；2)各gaba能神经元DNMT1表达升高与reelin、GAD67表达降低一致；3) DNMT1表达升高，reelin和GAD67表达降低也延伸至双相情感障碍患者的大脑；4) DNMT1与组蛋白去乙酰化酶和组蛋白甲基化酶等复合物建立了伙伴关系，这是两种重要的酶，用于调节组蛋白控制转录因子或DNMT1对基因启动子中靶向调控位点的可及性。更好地了解表观遗传机制如何调节reelin和GAD67基因转录，可能有助于发现新的药物靶点，这些靶点可以重编程转录，并可能改变与表观遗传诱导的SZ基因表达下调相关的病理。