Loss of the Intellectual Disability and Autism Gene and Its Homolog Differentially Affect Spatial Memory, Anxiety, and Hyperactivity

Hundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold cause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that -deficient mice present with cognitive and social deficits, hyperactivity and anxiety. In Drosophila, loss of the only ortholog of , is embryonically lethal, while in vertebrates, has a homolog which appears to be compensating, indicating that and have a redundant function in humans and mice. Here, we generate an allelic series of and LOF to determine the relative role of these genes during behavioral development. We generated knockout (KO), double heterozygous and double KO mice, then performed behavioral studies to analyze learning and memory, social interactions, anxiety, and hyperactivity. We found that and have partially overlapping roles. Overall, loss of is less severe than loss of , only leading to cognitive deficits, while double heterozygous animals are similar to -deficient mice. These results will help us better understand the deficits in individuals with mutations, suggesting that recessive mutations and -heterozygous and mutations could also contribute to the genetics of ID.