SHANK3基因甲基化水平改变与精神分裂症发病机制的相关研究

Schizophrenia is one of the most severe neuropsychiatric disorders, the etiological and pathophysiological basis of which are poorly understood. As a kind of epigenetic modification, DNA methylation was hereditary and responsive to environmental factors, which may play an important role in pathophysiology of schizophrenia. In our previous study, we found that the methylation level of SHANK3 promoter increased significantly in the peripheral blood monouclear cells (PBMCs) of schizophrenia patients, together with the abnormal brain structure by structural magnetic resonance imaging (MRI) analysis. Meanwhile, the methylation level of SHANK3 gene was correlative with brain structure. The hypothesis of abnormal glutamate has attracted increasing attention in the pathophysiological study of schizophrenia. As the scaffolding protein of the postsynaptic platform at postsynaptic density (PSD), SHANK3 integrated with N-methyl-D-aspartate (NMDA) receptor, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mGlu receptors. SHANK3 participated in modulating dendritic spine morphology and synaptic signaling through glutamate receptors and interactions with the cytoskeleton. In the proposed study, we establish a translational model of ErbB4-/- mice to investigate the important affects of SHANK3 methylation level on the abnormal brain structure of schizophrenia, accompanied with social isolation as the environmental factor, and further to investigate the mechanism of glutamate underlying the schizophrenia. The ErbB4-/- mice was considered as the authoritative model of schizophrenia, while the social isolation might mimic separation from parents and family members in humans, critically affects their adult behavioral patterns relative to those of mice raised in normal group housing. The translational model surmounts the clinical limitations and allows synchronal research of schizophrenia in both human patients and animal models from the molecular to systematic level. The results from this research are respected to further understand the pathogenesis of schizophrenia, to develop new means of disease prevention, and to provide the scientific basis for disease diagnosis and target treatment.

精神分裂症是临床常见的重性精神疾病，病因机制不清。研究表明DNA甲基化可以稳定遗传也会在环境刺激下产生响应性变化，可能在精神分裂症的发病过程中发挥重要作用。谷氨酸异常假说在精神分裂症病因学的研究中日益受到重视。支架蛋白SHANK3在兴奋性突触后与多种谷氨酸受体分子相互作用，参与突触信号传递等重要过程，因此SHANK3基因功能改变可能是影响精神分裂症发病的重要因素之一。申请人及研究团队拟在前期深入分析SHANK3基因甲基化水平改变对首发未治疗精神分裂症患者脑结构异常影响的基础上，通过建立“人－动物”转化研究模式，采用多模态多层次的研究策略，以公认的ErbB4-/-小鼠为精神分裂症模型动物，以社会隔离作为环境刺激，深入探讨SHANK3基因参与的谷氨酸能神经元调节功能紊乱在精神分裂症发病机制中的重要作用。本研究有望为深入理解精神分裂症的发病机制，并为精神分裂症诊断和治疗提供新的思路。