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

精神分裂症患者对感染抗原和食物抗原的体液免疫能力增强。增加了 在个体中发现补体激活和循环免疫复合体(CIC)水平升高 得了这种病。结合这些复合体的补体因子C1q也在 发育中皮质中的突触位置。项目6将检验这一假设 DISC1突变小鼠表现出大脑中C1q激活增加。此外，我们预测，早些时候 出生后暴露于环境诱因，如弓形虫感染，将进一步加剧 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 发育中的额叶皮质的缺陷。大量病例对照采集的血液和脑脊液 疾病的不同阶段结合匹配的死后血清和额叶皮质样本将 允许对人类样本与DISC1突变小鼠进行平行研究。 特定目标1将检验这样一个假设，即在模型抗原酪蛋白穿过胃肠道后 屏障，C1q相关的免疫复合体形成，在人类样本中留下分子特征， 从外围到中枢神经系统都可以追溯到。 特定目标2将评估大脑中与CIS相关的补体系统激活的假说 出生后早期感染弓形虫会加剧DISC1突变小鼠的病情，导致 额叶皮质内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.