Targeting Notch Signaling to Restore Neural Development and Behavior in Autism
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors, influenced by both genetic and environmental factors. However, the molecular mechanisms underlying this heterogeneity remain unclear. This study highlights dysregulation of the Notch signaling pathway as a shared molecular mechanism in inherited and non-hereditary ASD models in mice and humans. Aberrant HDAC3-mediated epigenetic activation of Notch signaling during embryonic forebrain development disrupts the specification of caudal ganglionic eminence (CGE) precursors into VIP+ GABAergic interneuron subtypes (VIP-INs). CGE-specific ablation of Notch1/2 genes in ASD models rescues the VIP-IN loss, E/I balance, and selectively improves social behaviors. Remarkably, a single antenatal dose of a ?-secretase inhibitor, previously used in the clinical trials for cancer treatment, effectively ameliorates multiple ASD-associated neuronal, behavioral, and transcriptomic levels in adult models. Thus, the study confers a critical convergence of ASD risk factors on Notch signaling dysregulation and establishes this pathway as a promising therapeutic target for developmental and behavioral deficits in ASD. Overall design: Pregnant mice received intraperitoneal (i.p.) injections of VPA at E13, E15, or E18. To assess rescue effects, Ro4929097 was administered at E17. Offspring were analyzed at P2.