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Targeting Notch Signaling to Restore Neural Development and Behavior in Autism

ABSTRACT: 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 γ-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE292235 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Developmental exposure to environmental pollutants is increasingly recognized as a significant risk factor for autism spectrum disorder (ASD), yet the specific mechanisms by which individual toxicants contribute to this neurodevelopmental disorder remain largely unknown. Methyl ester sulfonate (MES), a widely used anionic surfactant with widespread environmental detection, lacks comprehensive evaluation for developmental neurotoxicity. Here, we exposed pregnant mice to environmentally relevant MES doses (0.06–6 mg/L) from gestational day 8.5 (GD8.5) to postnatal day 21.5 (PND21.5) and assessed their offspring for neurodevelopmental changes. Results showed dose-dependent ASD-like behavioral deficits, including impaired social interactions, heightened anxiety-like behaviors, and increased repetitive/stereotypic patterns. These behavioral anomalies were accompanied by neuropathological alterations, including blood-brain barrier (BBB) disruption, neuronal loss, and reduced dendritic spine density, indicative of impaired synaptogenesis. Integrative transcriptomic analysis of hippocampal tissue revealed significant dysregulation of key pathways involved in neurodevelopment, prominently featuring the Notch/Hes signaling pathway. Molecular docking simulations suggested that MES could directly interactwith Notch receptors, potentially disrupting ligand-receptor interactions. Further in vitro experimental validation demonstrated that MES exposure suppressed neural stem cell differentiation. Collectively, these findings provided evidence that early-life MES exposure acts as a neurodevelopmental toxicant by disrupting Notch/Hes signaling, thereby impairing neuronal differentiation and synaptogenesis, which underlied the observed ASD-like behavioral deficits in mice. This study offers novel mechanistic insights into how environmental factors contribute to ASD pathogenesis and highlights the need for toxicological assessment of widely distributed surfactants.

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Targeting Notch Signaling to Restore Neural Development and Behavior in Autism

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