Summary

Microglia-mediated neuroinflammation is increasingly recognized as a key pathological component in autism spectrum disorders (ASDs), though the mechanisms driving microglial activation remain largely elusive. Our study reveals that deficiency in the high-risk ASD gene SETDB1, as well as maternal immune activation (MIA), elevates complement protein C4b expression specifically in prefrontal cortex (PFC) neurons. This upregulation triggers excessive microglial synaptic pruning, leading to autistic-like behaviors. Furthermore, we found that microglia elimination improved synaptic density, while complete C4b knockout rescued all observed autistic-like phenotypes in mice. C4b expression is driven by RNA-DNA hybrids formed through the reactivation of endogenous retroviruses (ERVs). Notably, we identify that existing FDA-approved HIV medications, which inhibit retrotranscriptional activity, substantially reduce C4b levels and alleviate ASD symptoms. These findings underscore the crucial role of C4b in microglia-mediated synaptic pruning in ASD and highlight the therapeutic potential of targeting ERV reactivation with existing HIV medications.