Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.

中文翻译：

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精神分裂症相关基因C4的表达增加导致前额叶皮层连通性降低和社会互动减少。

精神分裂症是一种严重的精神疾病，病理生理尚不清楚。免疫基因C4的表达增加与罹患精神分裂症的更大风险有关。然而，尚不清楚C4在这种脑部疾病中是否起病因作用。使用共聚焦成像和全细胞电生理学，我们证明了小鼠前额叶皮层神经元中C4的过度表达导致树突棘发育和连接性低下的摄动，这反映了精神分裂症患者的神经病理学。我们发现证据表明，小胶质细胞介导的突触吞噬随着C4表达的增加而增强。我们还表明，额叶皮层中C4依赖的电路功能障碍导致幼年和成年小鼠的社交互动减少。