少突胶质细胞及其分化调控因子Olig2在精神分裂症发生中的作用机制研究

Schizophrenia is a major psychiatric disorder and the etiology of it is still unclear at present. The previous studies showed that the abnormalities of oligodendrocytes(OLS) and oligodendrocyte precusor cells(OPC) were found in the brains of patients with schizophrenia. In addition, as the critical regulator factor for the differentiation of OPC to OLS, Olig2 gene, was also altered in schizophrenia.Our previous study also found that the methylation level in the promoter of Olig2 gene from the peripheral blood of schizophrenia was significantly higher than that from the controls. However, it is still unknown whether it is a primary or secondary change about the OLS damage and abnormal regulation of Olig2 in the differentiation of OLS in the pathogenesis of schizophrenia. In the study, based on the basis of our previous experiments, the conditional mice with expression of diphtheria toxin protein and the knockout mice with the deletion of Olig2 gene in OPC will be used as the targeted animals. The behavior changes of mice from behavior experiments, and prepulse inhibition (PPI) missing which is the characteristic changes of electrophysiology in the schizophrenic, would be used as the evaluation index. The immunofluorescence, in situ hybridization and electrophysiological techniques would be applied to explore the roles of OLS death in the specific brain regions of mice and the abnormal regulation of Olig2 during the differentiation and maturation of OLS in the incidence of schizophrenia-like symptoms and PPI missing. The aim of the study is to obtain direct evidence to explore the exact relationship between the changes of the OLS damage and Olig2 gene abnormal regulation of OPC differentiation and schizophrenia, and also provide the valid evidence in order to ultimately uncover the etiology of the complicated disease.

精神分裂症是一种重性精神障碍，其病因至今未明。研究发现，该症患者尸脑组织少突胶质细胞（OLS）及其前体细胞（OPC）存在异常，且调控OPC分化成熟为OLS的决定性因子Olig2也存在异常。申请人既往研究发现，该症患者外周血Olig2基因启动子区甲基化水平异常升高。但OLS损害及Olig2基因异常调控OPC分化是该症发生的原发改变还是继发改变，至今不清。本课题在前期实验基础上，利用已制备的条件性白喉毒素A片段表达小鼠和OPC中Olig2基因敲除小鼠，以小鼠行为学和分裂症特征性改变即前脉冲抑制（PPI）缺失为评价指标, 应用免疫荧光、原位杂交及电生理等技术，探讨小鼠脑特定部位OLS异常及Olig2基因异常调控OPC分化成熟在精神分裂样症状产生及在PPI缺失机制中的作用。通过本研究，期望获取OLS损害及Olig2基因异常调控与精神分裂样症状产生间因果关系的直接证据，为该症病因学研究提供科学依据。

精神分裂症是一种重性精神障碍，其病因至今未明。研究发现，该症患者尸脑组织少突胶质细胞（OLS）及其前体细胞（OPC）存在异常，且调控OPC分化成熟为OLS的决定性因子Olig2也存在异常。但OLS损害及Olig2基因异常调控OPC分化是该症发生的原发性改变还是继发性改变，至今不清。本课题在前期实验基础上，利用已制备的条件性白喉毒素A片段表达小鼠和OPC中Olig2基因敲除小鼠，以小鼠行为学和分裂症特征性改变即前脉冲抑制（PPI）为评价指标,探讨小鼠脑特定部位OLS异常及Olig2基因异常调控OPC分化成熟在分裂样症状产生及在PPI缺失机制中的作用。本研究发现：与海马区(497.76±6.70cm)和胼胝体区(447.31±17.20cm)注入生理盐水的小鼠相比，Tamaxifen注射小鼠在旷场中心移动距离显著增多（761.52±11.38cm，P<0.05；782.50±7.59cm，P<0.05）；与野生型小鼠相比(中心区1:18.97±0.93; 中心区2:16.83±1.13)， Olig2基因敲除小鼠在中心区域运动的时间较多(中心区1: 29.52±0,58, P<0.05; 中心区2: 28.66±1.11，P<0.05)；与野生型小鼠相比，少突胶质细胞前体细胞Olig2基因敲除小鼠在76dB（P<0.05)和82dB（P<0.01）前脉冲信号出现时对惊跳反应的抑制显著变少；电镜检查结果，与正常对照组相比，Olig2基因敲除组小鼠视神经和胼胝体的髓鞘化轴突数量减少（P<0.05）。本研究为精神分裂症的病因学研究和该疾病的治疗靶点提供了重要的科学依据。