GABAergic molecular pathology in schizophrenia

精神分裂症的 GABA 分子病理学

• 批准号: 7034548
• 负责人: ERMINIO COSTA
• 金额: $ 30.27万
• 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/7034548
• 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）：前额叶皮层（RFC）GABA能中间神经元是与精神分裂症（SZ）发病相关的分子病理学的主要靶点;它们的改变可能有助于减少皮质神经元凋亡，这是SZ病理生理学的重要组成部分。皮层GABA能神经元通过在GABAA和GABAB受体上释放GABA参与皮层锥体神经元群体放电的协调，并通过由作用于位于树突棘突触后密度上的整联蛋白受体的reelin的GABA能神经元释放促进的棘驻留mRNA的翻译来调节树突棘可塑性。在SZ皮质GABA能神经元中，GABA和reelin的合成减少，这是因为GAQ 67和reelin mRNA表达下调。这很可能是由于GABA能神经元中DNA-（胞嘧啶5）-甲基转移酶1（DNMT 1）的表达增加所致，DNMT 1有助于在reelin和GAD 67基因中表达的CpG岛和启动子的表观遗传超甲基化，并导致这两种基因转录本的合成减少。因此，我们推测，由于表观遗传机制引起的GABA能功能下调可能是SZ发病的一个重要的主要过程。我们会研究：（1）除BA 9和BA 10外，在枕叶皮质和尾状核的GABA能神经元中，DNMT 1与reelin和GAD 67共表达，（2）在每个GABA能神经元中，DNMT 1表达的增加与reelin和GAD 67表达的减少相一致;（3）双相情感障碍患者脑内DNMT 1表达增加，reelin和GAD 67表达减少; 4）DNMT 1与包括组蛋白脱乙酰酶和组蛋白甲基化酶的复合物建立伙伴关系，这两种酶是调节密码子的两种重要酶，组蛋白借此控制转录因子或DNMT 1对基因启动子中靶向调节位点的可及性。更好地了解表观遗传机制如何调节reelin和GAD 67基因转录，可能会发现新的药物靶点，可以重新编程转录，并可能修改与表观遗传诱导的SZ基因表达下调相关的病理。