Autism spectrum disorder traits in Slc9a9 knock-out mice

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders which begin in childhood and persist into adulthood. They cause lifelong impairments and are associated with substantial burdens to patients, families, and society. Genetic studies have implicated the sodium/proton exchanger (NHE) nine gene, Slc9a9, to ASDs and attention-deficit/hyperactivity disorder(ADHD). Slc9a9 encodes, NHE9, a membrane protein of the late recycling endosomes. The recycling endosome plays an important role in synapse development and plasticity by regulating the trafficking of membrane neurotransmitter receptors and transporters. Here we tested the hypothesis that Slc9a9 knock-out (KO) mice would show ADHD-like and ASD-like traits. Ultrasonic vocalization (USV) recording showed that Slc9a9 KO mice emitted fewer calls and had shorter call durations, which suggest communication impairment. Slc9a9 KO mice lacked a preference for social novelty, but did not show deficits in social approach; Slc9a9 KO mice spent more time self-grooming, an indicator for restricted and repetitive behavior. We did not observe hyperactivity or other behavior impairments which are commonly comorbid with ASDs in human, such as anxiety-like behavior. Our study is the first animal behavior study that links Slc9a9 to ASDs. By eliminatingNHE9 activity, it provides strong evidence that lack of Slc9a9leads to ASD-like behaviors in mice and provides the field with a new mouse model of ASDs.