ERV-Derived RNA-DNA Hybrids Upregulate C4b to Induce Microglial Synaptic Pruning in autism [ChIP-seq]

Microglia-mediated neuroinflammation has been identified as pathogenic in autism spectrum disorders (ASD). Pathogenic factors for microglial activation remain unclear. In our study, we discovered that complement C4b is highly expressed in the prefrontal cortex (PFC) neurons with SETDB1 deficiency, a high-risk gene of ASD, or by maternal inflammation (MI). Exposure to C4b led microglia to perform excessive synaptic pruning, which in turn manifested ASD-like phenotypes. Furthermore, we observed that removing microglia could improve synaptic functions, while the complete knockout of C4b could rescue all observed autistic phenotypes. The expression of C4b was contingent upon RNA-DNA hybrids formed by the reactivation of Endogenous Retroviruses (ERVs). Interestingly, the pharmacological reversal of this retrotranscriptional process with FDA-approved HIV medications significantly reduced C4b levels and ameliorated the symptoms of ASD. Our findings illuminate the pivotal role of C4b in microglia-driven synaptic pruning linked to ASD and suggest that targeting ERV reactivation could be a promising therapeutic strategy with existing FDA-approved HIV drugs.