Duplication of autism-related gene Chd8 leads to behavioral hyperactivity and neurodevelopmental defects in mice

Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders. Overall design: RNA-seq analysis in the forebrain from mice at E14.5 and E18.5 (quintuplicate; Chd8 WT vs. KI), ChIP-seq analysis with antibody to CHD8 in the forebrain from mice at E14.5 (triplicate; Chd8 WT vs. KI), ATAC-seq analysis in the forebrain from mice at E14.5 (quadruplicate; Chd8 WT vs. KI).