GABAergic molecular pathology in schizophrenia

描述(申请人提供)：前额叶皮质(RFC)GABA能中间神经元是精神分裂症(SZ)发病相关分子病理学的主要靶点；它们的改变可能有助于皮质神经纤维的减少，这是SZ病理生理学的重要组成部分。皮质GABA能神经元通过GABAA和GABAB受体上GABA的释放参与皮质锥体神经元群体放电的协调，并通过GABA能神经元释放作用于树突棘突触后密度上整合素受体的reelin，通过翻译驻留在脊椎上的mRNAs来调节树突棘的可塑性。在SZ皮质GABA能神经元中，由于GAQ67和Reelin基因表达下调，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Reelin和GAD67基因中表达的CpG岛和启动子的表观遗传超甲基化，从而导致这两个基因转录本的合成减少。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)除了BA9和BA10 GABA能神经元外，DNMT1在枕叶皮质和尾状核的GABA能神经元中是否与reelin和GAD67共表达；2)在每个GABA能神经元中，DNMT1表达的增加与reelin和GAD67表达的降低是一致的；3)DNMT1的表达增加以及reelin和GAD67表达的降低也延伸到双相情感障碍患者的大脑；4)DNMT1与包括组蛋白脱乙酰酶和组蛋白甲基酶在内的复合体建立了合作伙伴关系，这两种酶可以调节密码，从而控制组蛋白可以控制转录因子或DMTN1对基因启动子中靶向调控位点的可及性。更好地理解表观遗传机制如何调控reelin和GAD67基因转录，可能会发现新的药物靶点，可以重新编程转录，或许还可以修改与表观遗传诱导的SZ基因表达下调相关的病理。

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.