Targeting Notch Signaling to Restore Neural Development and Behavior in Autism
Preprint
- 23 April 2025
- preprint
- Published by Springer Nature in Research Square
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with diverse genetic and environmental origins, yet whether these factors converge on common molecular pathways remains unclear. Here we identify dysregulation of the Notch signaling pathway as a shared mechanism in both hereditary and non-hereditary ASD models. Aberrant HDAC3-mediated epigenetic regulation of Notch signaling during embryonic forebrain development disrupts the specification of caudal ganglionic eminence (CGE) progenitors into VIP+ GABAergic interneuron subtypes (VIP-INs). CGE-specific ablation of Notch1/2 genes in ASD models restores the loss of VIP-INs and E/I imbalance, and selectively improves social behaviors. Remarkably, a single antenatal dose of a γ-secretase inhibitor ameliorates multiple ASD-associated neuronal, behavioral, and transcriptomic changes in adult models. Thus, this study confers a strong convergence of ASD-related factors on Notch signaling dysregulation and establishes this pathway as a promising therapeutic target for developmental and behavioral deficits in ASD.Keywords
All Related Versions
- Version 1, 2025-04-23, Research Square
- Published version: Nature Communications, 17 (1).
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