{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:38:21Z","timestamp":1768520301387,"version":"3.49.0"},"posted":{"date-parts":[[2025,2,19]]},"group-title":"Neuroscience","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  In autism spectrum disorder (ASD), a neurodevelopmental disorder with social-cognitive deficits, macrocephaly occurs in 20% of patients with severe symptoms. However, the role of macrocephaly in ASD pathogenesis remains unclear. Here, we address the mechanistic link between macrocephaly and ASD by investigating a novel ASD-associated gain-of-function A1877T mutation in\n                  <jats:italic>ASPM<\/jats:italic>\n                  (\n                  <jats:italic>abnormal spindle-like microcephaly-associated<\/jats:italic>\n                  ).\n                  <jats:italic>ASPM<\/jats:italic>\n                  is a key regulator of cortical size and cell proliferation expressed in both excitatory and inhibitory neuronal progenitors but not in differentiated neurons. We found that\n                  <jats:italic>Aspm<\/jats:italic>\n                  gain-of-function knock-in mice exhibit macrocephaly, excessive embryonic neurogenesis with expanded outer radial glia, an increased excitatory-inhibitory (E-I) ratio, brain hyperconnectivity, and social-cognitive deficits with male specificity. Our results suggest that macrocephaly in ASD is not a proportional expansion of excitatory and inhibitory neurons, but a shift in the E-I ratio, independent of the expression patterns of the causative gene. Thus, macrocephaly alone can cause a subset of ASD-like symptoms.\n                <\/jats:p>","DOI":"10.1101\/2025.02.17.638753","type":"posted-content","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T07:35:13Z","timestamp":1739950513000},"source":"Crossref","is-referenced-by-count":0,"title":["Autism-associated\n                  <i>ASPM<\/i>\n                  variant causes macrocephaly and social-cognitive deficits in mice"],"prefix":"10.64898","author":[{"given":"Sonu","family":"Singh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyopil","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alev","family":"Ecevitoglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renee","family":"Chasse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis 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