Sex-Dependent Motor Deficit and Increased Anxiety-Like States in Mice Lacking Autism-Associated Gene Slit3

Abstract

Altered neuronal connectivity has been implicated in the pathophysiology of Autism Spectrum Disorder (ASD). SLIT/ROBO signaling plays an important role in developmental processes of neuronal connectivity, including axon guidance, neuronal migration, and axonal and dendritic branching. Genetic evidence supports that <i>SLIT3</i>, one of the genes encoding SLITs, is associated with ASD. Yet the causal link between <i>SLIT3</i> mutation and autism symptoms has not been examined. Here we assessed ASD-associated behaviors in <i>Slit3</i> knockout (KO) mice. Our data showed that <i>Slit3</i>-KO mice exhibited reduced marble burying behaviors but normal social behaviors. In addition, <i>Slit3</i>-KO mice displayed hypolocomotion in the open field test and impaired motor coordination in the rotarod test. Anxiety-like behaviors were mainly observed in female KO mice assessed by three types of behavioral tests, namely, the open field test, elevated plus maze test, and light/dark box test. No differences were observed between KO and wildtype mice in recognition memory in the novel object recognition test or depression-like behavior in the tail suspension test. Taken together, loss of <i>Slit3</i> may result in disrupted neural circuits related to motor function and increased anxiety-like states, which are co-occurring symptoms in ASD.