PBRM1 Deficiency in Microglia Leads to Excessive Neurogenesis and Autism-Like Behaviors via the CCL5-CCR1/5-β-catenin Signaling Axis.

Authors

Yang-Yang Duan, Lin-Fei Jiao, Pei-Pei Liu, Chun-Hui Duan, Xiao Li, Zi-Han Zhang, Yue-Qi Zhang, Xin-Li Ouyang, Hong-Zhen Du, Sha Liu, Yi Tang, Zhao-Qian Teng, Chang-Mei Liu

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e78086. Oct 18, 2026. Epub Oct 18, 2026.

Abstract

The prevalence of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder with limited effective therapeutic drugs, has been rising worldwide. Missense mutations in Polybromo 1 (Pbrm1), a core component of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex, have been identified as a risk factor for ASD; however, whether PBRM1 loss of function contributes to the pathogenesis remains elusive. Here we provide direct evidence that microglial PBRM1 deficiency leads to altered microglial clusters, excessive neurogenesis, and ASD-like behaviors in mice. Integrated molecular analyses reveal that PBRM1 directly binds to the Ccl5 promoter and represses the expression of CCL5. Elevated CCL5 promotes the proliferation and neuronal differentiation of neural stem/progenitor cells (NSPCs) via the CCR1/5-β-catenin signaling pathway. Importantly, pharmacological blockade of CCR1/5 ameliorates behavioral deficits in Pbrm1 cKO mice. Together, these findings identify a previously unrecognized microglia-NSPC communication mechanism linking PBRM1 dysfunction to aberrant neurodevelopment and suggest the CCL5-CCR1/5 axis as a potential therapeutic target for ASD.

PMID:
42893407
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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