Targeting Notch Signaling to Restore Neural Development and Behavior in Autism

Targeting Notch Signaling to Restore Neural Development and Behavior in Autism | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Targeting Notch Signaling to Restore Neural Development and Behavior in Autism Takatoshi Iijima, Yoko Hanno, Moe Nakanishi, Akinori Takase, Jun Nomura, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6343474/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Mar, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version 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. Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders Biological sciences/Neuroscience/Epigenetics in the nervous system/Epigenetics and behaviour Biological sciences/Neuroscience/Development of the nervous system/Cell fate and cell lineage Biological sciences/Neuroscience/Social behaviour Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTables.xlsx Supplemantary tables 1-4 Cite Share Download PDF Status: Published Journal Publication published 30 Mar, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6343474","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":440456101,"identity":"4cc70fac-6a09-4ebe-b216-3604dd348a83","order_by":0,"name":"Takatoshi 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