Neuroimmune interactions play a significant role in regulating synaptic plasticity in both the healthy and diseased brain. The complement pathway, an extracellular proteolytic cascade, exemplifies these interactions. Its activation triggers microglia-dependent synaptic elimination via the complement receptor 3 (CR3). Current models of pathological complement activity in the brain propose that accelerated synaptic loss resulting from overexpression of C4 (C4-OE), a gene associated with schizophrenia, follows this pathway. Here, we report that C4-mediated cortical hypoconnectivity is CR3-independent. Instead, C4-OE triggers impaired GluR1 trafficking through an intracellular mechanism involving the endosomal protein SNX27, resulting in pathological synaptic loss. Moreover, C4 circuit alterations in the prefrontal cortex, a brain region associated with neuropsychiatric disorders, were rescued by increasing neuronal levels of SNX27, which we identify as an interacting partner of this neuroimmune protein. Our results link excessive complement activity to an intracellular endo-lysosomal trafficking pathway altering synaptic plasticity.

神经免疫相互作用在调节健康和患病大脑的突触可塑性方面发挥着重要作用。补体途径（细胞外蛋白水解级联）例证了这些相互作用。它的激活通过补体受体 3 (CR3) 触发小胶质细胞依赖性突触消除。目前大脑中病理补体活动的模型表明，C4（C4-OE）（一种与精神分裂症相关的基因）过度表达导致突触损失加速，遵循这一途径。在这里，我们报告 C4 介导的皮质连接低下是 CR3 独立的。相反，C4-OE 通过涉及内体蛋白 SNX27 的细胞内机制触发 GluR1 运输受损，导致病理性突触损失。此外，前额皮质（与神经精神疾病相关的大脑区域）中的 C4 回路改变可以通过增加 SNX27 的神经元水平来挽救，我们将 SNX27 确定为这种神经免疫蛋白的相互作用伙伴。我们的结果将过度的补体活性与改变突触可塑性的细胞内溶酶体运输途径联系起来。