PBRM1 Deficiency in Microglia Leads to Excessive Neurogenesis and Autism‐Like Behaviors via the CCL5‐CCR1/5‐β‐catenin Signaling Axis
Year: 2026
Type: article
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.
Source: Advanced Science
DOI: 10.1002/advs.78086
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
OpenAlex ID: W7222901236