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Endogenous retrovirus-derived RNA-DNA hybrids induce microglial synaptic pruning in autism models
Shaoxuan Chen1, Boxin Zhang1, Tianyu Qin2
1Department of Psychiatry of Sir Run Run Shaw Hospital, Institute of Immunology, Zhejiang University School of Medicine, Liangzhu Laboratory, Hangzhou 310058, China; MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
Neuron
|February 26, 2026
Summary
Deficiency in the autism spectrum disorder (ASD) gene SETDB1 or maternal immune activation increases C4b, causing excessive synaptic pruning and autistic behaviors. Targeting retroviral activity with HIV drugs reduced C4b and alleviated ASD symptoms.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Microglia-driven neuroinflammation is implicated in autism spectrum disorders (ASDs).
- Mechanisms underlying microglial activation in ASDs are not fully understood.
- The gene SETDB1 is a high-risk gene associated with ASDs.
Purpose of the Study:
- To investigate the role of SETDB1 deficiency and maternal immune activation (MIA) in ASD pathogenesis.
- To identify the molecular mechanisms linking genetic and environmental risk factors to autistic behaviors.
- To explore potential therapeutic targets for ASDs.
Main Methods:
- Studied SETDB1 deficiency and MIA models in mice.
- Measured complement protein C4b expression in the prefrontal cortex (PFC).
- Assessed microglial synaptic pruning, synaptic density, and autistic-like behaviors.
- Investigated the role of RNA-DNA hybrids and endogenous retroviruses (ERVs).
- Tested the efficacy of microglia elimination and C4b knockout.
- Evaluated FDA-approved HIV medications targeting retrotranscriptional activity.
Main Results:
- SETDB1 deficiency and MIA elevated C4b expression in PFC neurons.
- Upregulated C4b led to excessive microglial synaptic pruning and autistic-like behaviors.
- Microglia elimination improved synaptic density; C4b knockout rescued phenotypes.
- C4b expression is driven by ERV reactivation via RNA-DNA hybrids.
- HIV medications reduced C4b levels and alleviated ASD symptoms in mice.
Conclusions:
- C4b plays a critical role in microglia-mediated synaptic pruning in ASD.
- ERV reactivation contributes to neuroinflammation and ASD pathogenesis.
- Targeting ERV reactivation with existing HIV medications shows therapeutic potential for ASDs.
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