辅助性T细胞17介导小胶质细胞活化与精神分裂症大鼠模型白质损伤的关系

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.

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。

本研究通过制备孕期感染PolyI:C和“二次打击”这两种精神分裂症动物模型，分析子代精神分裂症大鼠模型在不同发育阶段脑内胶质细胞、炎性相关细胞因子和脑白质的变化，同时也对于成年早期发病的精神分裂症患者脑白质进行影像学分析。结果显示：（1）孕期感染模型组子代大鼠在青春期和成年期的行为学方面均有异常表现；（2）给予抗精神病药物喹硫平及小胶质细胞抑制剂纳洛酮分别作为干预剂进行干预后孕期感染模型组的异常行为学（前脉冲抑制、被动规避、旷场活动）有一定改善；（3）“二次打击”模型子代大鼠在青春晚期稳定表现出类精神分裂症样行为：自发活动增加，焦虑情绪减轻，认知功能障碍。（4）孕期感染模型组青春期和成年期额叶和海马中Iba1标记的小胶质细胞数量增多，小胶质细胞均处于活化状态。成年期模型组大鼠额叶和海马区的GFAP标记的星形胶质细胞的光密度值升高，星形胶质细胞处于活化状态；（5）孕期感染模型组青春期和成年期大鼠额叶和海马脑匀浆中炎性细胞因子IL-6、IL-1β和TNF-α的蛋白水平浓度均有不同程度的升高；（6）孕期感染模型组胼胝体MBP免疫组化结果和LFB染色结果部分存在异常改变；且胼胝体MAGmRNA相对表达量增加；给以喹硫平进行干预后上述白质异常有所改善；（7）“二次打击”模型子代大鼠在青春晚期表现出外周和中枢存在炎性状态，主要表现为“二次打击”模型组的血浆IL-1β蛋白质表达水平、前额叶皮质和海马脑区脑组织中IL-6、IL-1β蛋白质表达水平升高，且海马区和前额叶皮质区小胶质细胞异常活化；（8）通过影像学分析，同健康对照组相比，成年早期发病的精神分裂症患者存在扣带束、胼胝体、内囊、上纵束及钩束等脑区白质改变，主要表现为FA降低和MD增高。本研究结果显示精神分裂症中中枢神经系统存在炎性改变，且在发育早期更为显著，同时伴有白质的损伤，这些异常在不同的药物干预下可有一定的改善，这些炎性改变通过导致脑白质的损伤，来诱导类精神分裂症样行为的发生，这或许是精神分裂症发生的重要通路。