Targeting Notch Signaling to Restore Neural Development and Behavior in Autism

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.