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Recent genetic studies have identified de novo loss\u2010of\u2010function (dnLoF) mutations in the <jats:italic>Down Syndrome Cell Adhesion Molecule (DSCAM)<\/jats:italic> as a strong risk factor for ASD. Previous research has shown that <jats:italic>DSCAM<\/jats:italic> ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent <jats:italic>DSCAM<\/jats:italic> underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of <jats:italic>DSCAM<\/jats:italic>, as in the <jats:italic>DSCAM<\/jats:italic><jats:sup>2J<\/jats:sup>+\/\u2212, that is, <jats:italic>DSCAM<\/jats:italic> heterozygous mice, displayed hyperactivity, increased anxiety\u2010like behavior, and motor coordination deficits. Additionally, hippocampal\u2010dependent learning and memory was affected, including impairments in working memory, long\u2010term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, <jats:italic>DSCAM<\/jats:italic> LoF produces autistic\u2010like behaviors that are similar to those observed in human cases of ASD. These findings further support a role for <jats:italic>DSCAM<\/jats:italic> dnLoF mutations in ASD and suggest <jats:italic>DSCAM<\/jats:italic><jats:sup>2J<\/jats:sup>+\/\u2212 as a suitable model for ASD research.<\/jats:p>","DOI":"10.1111\/gbb.70002","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T01:59:59Z","timestamp":1726711199000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cognitive behavioral phenotyping of <i>DSCAM<\/i> heterozygosity as a model for autism spectrum disorder"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6913-7561","authenticated-orcid":false,"given":"Ryan C.","family":"Neff","sequence":"first","affiliation":[{"name":"Michigan Neuroscience Institute, University of Michigan Medical School  Ann Arbor Michigan USA"},{"name":"Department of Molecular &amp; Integrative Physiology University of Michigan  Ann Arbor 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