中枢神经系统的免疫损伤是精神分裂症(SZ)发病机制研究的重要领域之一。既往研究提示SZ患者存在辅助性T细胞17(Th17)的过度增殖、小胶质细胞的活化以及脑白质的损害；但Th17增殖、小胶质细胞活化、脑白质损害三者间的关系并不清楚。本项目拟在前期工作基础上，重点开展以下2方面工作：1.以妊娠感染的子代大鼠为SZ动物模型，分析Th17细胞增殖相关信号通路分子的表达变化，了解小胶质细胞功能状态的改变，明确动物模型脑白质的损伤程度；2.利用工具药和抗精神病药物阻断模型动物Th17增殖和/或抑制小胶质细胞活性，对其能否改善脑白质受损和行为异常作出评价。本项目将从免疫调控、分子通路、脑结构与功能等层面系统探索Th17细胞增殖、小胶质细胞活化、白质损害三者之间的上下游关系；试图明确由于Th17增殖而激活小胶质细胞、继而导致脑白质损伤的机制。预期结果将为SZ免疫功能异常影响脑白质结构与功能提供实验证据。

Immune system abnormalities in schizophrenia have been one of the more enduring findings in the field, including aberrant cytokine levels and abnormal immune cell parameters both in peripher and central nervous system. The immune system dysfunction of central nervous system is regard as a important mechanism of pathophysiological studies in schizophrenia. T help cell 17 (Th17) was displayed more proliferative in schizophrenia patients compared with controll by our study and other publications. Previous studies have demonstrated that microglia activation is present in schizophrenia accompanied by brain damage. While increasing evidence suggests that damaged white matter is responsible for the clinical symptoms in schizophrenia. But the relationships among these pathological changes are still unknown. We will focus on the following two aspects in the present project based on previous works. On the one hand, the expression changes of molecules in pathway involved Th17 proliferation, function change of microglia, and lesion degree of white matter will be analyzed on maternal immune activation schizophrenia animal model. On the other hand, the Th17 proliferation and/or microglia activation will be blocked by various drugs to assess the improvements of white matter lesions and behavior abnormalities. In the present project, the relationship among Th17 cell proliferation, microglia activation and white matter lesions will be investigated systematically. The content include immune regulations, molecular pathways, and brain structures and functions. After this study, the mechanisms of white matter lesion caused by microglia activation induced by Th17 proliferation will be clarified in schizophrenia. The expected results would offer experimental evidences that the structures and functions of white matter can be affected by immune dysfunction in schizophrenia.