Cognitive behavioral phenotyping ofDSCAMheterozygosity as a model for autism spectrum disorder

Abstract

AbstractIt is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identifiedde novoloss-of-function (dnLoF) mutations in theDown Syndrome Cell Adhesion Molecule (DSCAM)as a strong risk factor for ASD. Previous research has shown thatDSCAMablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extentDSCAMunderexpression 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 ofDSCAM, as in theDSCAM2J+/− mice, displayed hyperactivity, increased anxiety, and motor coordination impairments. Additionally, hippocampal-dependent learning and memory was affected, including working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore,DSCAMLoF produces autistic-like behaviors that are similar to human cases of ASD. These findings further support a role forDSCAMdnLoF mutations in ASD and suggestDSCAM2J+/− as a suitable model for ASD research.Summary StatementAutism spectrum disorder represents a growing patient population. Loss of one copy of theDSCAMgene provides a promising mouse model that reproduces autistic-like behaviors for research and therapeutic testing.