Effects of Complement-lq Immune Activation on Synapse Formation in Schizophrenia

精神分裂症患者对传染性抗原和食物抗原的体液免疫增强。增加 在个体中发现补体激活和循环免疫复合物（CIC）水平增加 与这种疾病。结合这些复合物的补体因子C1q也高度表达， 发育中的皮层的突触位置。项目6将测试假设， DISC1突变小鼠显示大脑中C1q激活增加。此外，我们预测， 出生后暴露于环境触发因素，如弓形虫感染， DISC1突变小鼠脑内C1q激活对GABA中间神经元和脊髓密度的影响 发育中的额叶皮层有缺陷大量病例对照的血液和CSF采集， 疾病的不同阶段，结合匹配的死后血清和额叶皮质样本， 允许用DISC1突变小鼠对人类样本进行平行研究。 具体目标1将检验模型抗原酪蛋白通过GI渗透后的假设 屏障，形成C1q相关的免疫复合物，在人体样本中留下分子特征， 可从外周追踪到中枢神经系统。 具体目标2将评估以下假设：脑中CIS相关的补体系统激活 的DISC1突变小鼠在出生后早期感染弓形虫后， 额叶皮层GABA中间神经元和树突棘发育异常。

Individuals with schizophrenia have increased humoral immunity to infectious and food antigens. Increased complement activation and increased levels of circulating immune complexes (CIC) are found in individuals with this disease. The complement factor C1q that binds these complexes is also highly expressed at synaptic locations in the developing cortex. Project 6 will test the hypothesis that DISC1 mutant mice display increased C1q activation in the brain. Furthermore, we predict that early postnatal exposure to an environmental trigger such as Toxoplasma gondii infection will further exacerbate C1q activation in the brain of DISC1 mutant mice to contribute to GABA interneuron and spine density deficits in the developing frontal cortex. Extensive case-controlled collections of blood and CSF taken at various stages of disease in conjunction with matched post-mortem serum and frontal cortex samples will allow parallel studies of human samples with DISC1 mutant mice. Specific Aim 1 will test the hypothesis that following penetration of a model antigen, casein, through the GI barrier, C1q-associated immune complexes are formed, leaving molecular signatures in human samples that are traceable from the periphery to the CNS. Specific Aim 2 will evaluate the hypothesis that CIS-related activation of the complement system in the brain of DISC1 mutant mice will be exacerbated by early postnatal infection with Toxoplasma gondii, leading to abnormal development of GABA interneuron and dendritic spines in the frontal cortex.