The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development

Complement-mediated synapse elimination has emerged as an important process in both brain development and neurological diseases, but whether neurons express complement inhibitors that protect synapses against complement-mediated synapse elimination remains unknown. Here, we show that the sushi domain protein SRPX2 is a neuronally expressed complement inhibitor that regulates complement-dependent synapse elimination. SRPX2 directly binds to C1q and blocks its activity, andSRPX2(-/Y)mice show increased C3 deposition and microglial synapse engulfment. They also show a transient decrease in synapse numbers and increase in retinogeniculate axon segregation in the lateral geniculate nucleus. In the somatosensory cortex,SRPX2(-/Y)mice show decreased thalamocortical synapse numbers and increased spine pruning.C3(-/-);SRPX2(-/Y)double-knockout mice exhibit phenotypes associated withC3(-/-)mice rather thanSRPX2(-/Y)mice, which indicates that C3 is necessary for the effect of SRPX2 on synapse elimination. Together, these results show that SRPX2 protects synapses against complement-mediated elimination in both the thalamus and the cortex. The complement-microglia pathway is a key mediator of synapse elimination in development and disease. Cong et al. show that neurons endogenously express a complement inhibitor, SRPX2, that regulates synapse elimination in development.