脑海马组织特异SNAP25剔除的精神分裂症小鼠模型的构建及其表型分析

The incidence of Schizophrenia, a serious mutli-type psychotic disorder, has become an increasing trend. Although the pathophysiological mechanism(s) of schizophrenia has been poorly understood, it has been accepted to be closely associated with abnormalities in signaling transmission among neurons in the brain. The results from detection of sample with Schizophrenia, family pedigree, and whole genome-wide scan suggest that the synaptosomal-associated protein SNAP25 is highly coupled with schizophrenia and its expression is markedly downregulated in human hippocampus with Schizophrenia. Using a mouse model of SNAP25 gene knockout specially in hippocampus by Cre-lox-based conditional knockout, therefore, the present project is designed to determine the contribution of suppression of SNAP25 expression to organizational structure of cortex, function of neurotransmitter release in different ages and circumstances, and further elucidate if these changes are relative to behavior associated with schizophrenia. Results of this study will clarify the effect of abnormal function of hippocampal SNAP25 on organizational structure of cortex and synapse function and confirm the relationship between hippocampal SNAP25 and occurance of schizophrenia. Furthermore, this mouse model will be useful to comparatively determine the effect of inheritance, development, and circumstance on occurance of schizophrenia and provide the experimental foundation and theoretical warrant to explore the pathogenensis, diagnoses, and therapy of this disease.

精神分裂症是一类重型多发性精神疾病，发病率呈逐年上升趋势。尽管其病理生理学机制尚未阐明，但已证实与脑神经元间信号传递功能异常密切相关。对精神分裂症患者样本检查、家族系谱分析和全基因组扫描的结果提示：突触相关蛋白SNAP25基因与精神分裂症高度连锁、精神分裂症患者脑海马区该基因表达明显下调。据此，本课题设计利用基于Cre-loxP系统的基因条件打靶技术，构建脑海马SNAP25特异性剔除的小鼠模型，检测个体脑海马SNAP25的表达抑制在不同年龄期、不同环境下对大脑组织结构、神经突触递质释放功能的影响，分析其与精神分裂症相关的行为学改变。通过本工作，不仅将了解脑海马SNAP25功能异常对脑形态结构与突触功能的影响、明确其与精神分裂症发病之间的关系；同时，该小鼠将为进一步分析比较遗传、发育和环境对精神分裂症发病的影响提供研究用动究用动物模型，为探索疾病发病机制及诊断治疗奠定实验基础和理论依据。

Snap25 是神经元突触间信号传递的核心蛋白之一。不仅在神经胞吐的质膜融合过程中起着关键性作用，同时研究证实其与精神分裂症高度连锁、精神分裂症患者脑海马区该基因表达明显下调。本课题研究目标在于构建Snap25脑海马特异性条件剔除小鼠模型，分析Snap25表达异常对模型小鼠脑海马组织形态结构的影响。经过本年度工作，已构建获得Snap25脑海马特异性条件剔除小鼠模型；基因表达水平分析证实了模型小鼠脑海马Snap25表达水平的显著性下调；观察到Snap25脑海马表达缺失导致小鼠成活率下降。后续将进一步分析Snap25功能缺失对大脑海马组织结构、个体生理机能以及与精神分裂症发病之间的关系。该小鼠将为进一步分析比较遗传、发育和环境对精神分裂症发病的影响提供研究用动究用动物模型，为探索疾病发病机制及诊断治疗奠定实验基础和理论依据。