Aberrant neural stem cell quiescence is the gateway to autism development linked to Arid1b

Abstract

Autism spectrum disorder is a neurodevelopmental disorder with social communication deficits, repetitive behaviors, and restricted interests. While previous studies have demonstrated a close link between aberrant neurogenesis and the development of autism, a fundamental question remains unresolved: Does the anomalous neurogenesis observed in autism serve as a causative factor, and if so, could restoring aberrant neurogenesis alleviate autistic behaviors? In this study, we demonstrate that the manifestation of autistic behaviors can be caused by the aberrant activity of quiescent neural stem cells (qNSCs), resulting from the conditional deletion of Arid1b in adult brain NSCs. Particularly, increased H3K27me3 levels in qNSCs due to conditional Arid1b deficiency precipitated autism-related phenotypes, but rescuing this through H3K27me3 inhibition effectively reversed autistic-like phenotypes. Importantly, we also found quiescent like NSCs in humans carrying the ARID1B mutation, as well as in NSCs of sporadic autism patients. These results highlight the significant role of aberrant qNSCs associated with adult neurogenesis for autism development in adult brain, offering a novel avenue for potentially controlling qNSC activity as a therapeutic strategy for autism. © 2025 Elsevier B.V., All rights reserved.