Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits in Mice

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disease that has intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD) as its common comorbidities. Recent genetic and clinical studies report that <i>KDM6B</i>, a gene encoding a histone H3 lysine 27-specific demethylase, is one of the highest ASD risk genes. However, the relationship between <i>KDM6B</i> mutations and neurodevelopmental diseases remains unclear. Here we use an animal model to show that genetic deletion of one <i>Kdm6b</i> allele in mice leads to autistic-like impaired sociability and object recognition memory. In addition, the mutant mice display markedly increased locomotor activity and impulsivity, two ADHD-like behavioral traits that are ameliorated by methylphenidate treatment. Thus, our study not only uncovers a potential causal link between disruptive <i>KDM6B</i> mutations and ASD/ADHD-like behavioral deficits but also provides a new mouse model for studying the cellular and molecular mechanisms underlying the <i>Kdm6b</i>-mutation-related neurodevelopmental diseases.