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Genome\u2010wide association studies (GWAS) have identified the \u03b15 nicotinic acetylcholine receptor (\u03b15\u2010nAChR) subunit as a significant risk factor for these neuropsychiatric conditions. The \u03b15 subunit is a critical modulator of neural circuit dynamics, specifically through its functional involvement within vasoactive intestinal peptide (VIP)\u2010positive interneurons; however, its role in the sex\u2010dependent maturation of behavioral phenotypes remains poorly understood. We characterized \u03b15\u2010nAChR knockout (ACNA5) mice to investigate the neurodevelopmental consequences of \u03b15 subunit loss. ACNA5 mice displayed sexually dimorphic and age\u2010dependent core symptoms relevant to ASD and schizophrenia. Regarding anxiety\u2010like behavior, there was an opposite sex pattern between genotypes, evident only in adulthood. Cognitive assessment using the novel object location task revealed early\u2010onset spatial memory deficits in ACNA5 females, whereas males exhibited a progressive decline from adolescence to adulthood. In the social domain, adult ACNA5 mice failed to exhibit social novelty preference; females displayed complete social indifference, while males displayed a pronounced familiarity bias. In addition, ACNA5 mice of both sexes displayed amplified repetitive behavior, emerging earlier in males, and poor nest\u2010building scores across developmental stages. Together, these findings identify the \u03b15\u2010nAChR subunit as a crucial modulator of the maturation of neural circuits underlying social motivation, cognition, and emotional regulation. Our results implicate \u03b15\u2010containing nicotinic receptors in the pathogenesis of neurodevelopmental disorders and establish the ACNA5 mouse as a valuable model for investigating sex\u2010specific developmental trajectories and therapeutic windows.<\/jats:p>","DOI":"10.1002\/jnr.70156","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:53:28Z","timestamp":1791269608000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex\u2010Dependent Alterations in Behavioral Development of Mice Lacking \u03b15\u2010Nicotinic Acetylcholine Receptors"],"prefix":"10.1002","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9388-0109","authenticated-orcid":false,"given":"Danai","family":"Papavranoussi Daponte","sequence":"first","affiliation":[{"name":"Center for Basic Science Biomedical Research Foundation of the Academy of Athens  Athens Greece"},{"name":"Department of Biology National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4772-2864","authenticated-orcid":false,"given":"Filippos","family":"Marinos","sequence":"additional","affiliation":[{"name":"Center for Basic Science Biomedical Research Foundation of the Academy of Athens  Athens Greece"},{"name":"Department of Biology National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Matala","sequence":"additional","affiliation":[{"name":"Center for Basic Science Biomedical Research Foundation of the Academy of Athens  Athens Greece"},{"name":"Department of Biology National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7528-7208","authenticated-orcid":false,"given":"Irini","family":"Skaliora","sequence":"additional","affiliation":[{"name":"Center for Basic Science Biomedical Research Foundation of the Academy of Athens  Athens Greece"},{"name":"Department of History and Philosophy of Science National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/09540261.2010.515205"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3791\/50978"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149\u20107634(99)00034\u20102"},{"key":"e_1_2_12_5_1","doi-asserted-by":"crossref","unstructured":"Bailey C. 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