Uncoupling memory impairments from autism-associated behaviors in Chd2 deficient mice

Mutations in the chromatin remodeler, CHD2, are strongly associated with moderate to severe intellectual disability, autism and epilepsy, but the direct contribution of CHD2 mutations to clinical phenotypes is poorly understood. We report developmental and sex-specific behavioral changes in mice carrying a heterozygous mutation in Chd2. Notably, Chd2 mutants display a range of abnormal behaviors including impairments in multiple forms of memory and social interaction. Memory impairments and memory-relevant transcriptional changes observed in Chd2^+/- mice are largely recapitulated in both sexes by conditional Chd2^+/- in adulthood. However, deficits in social behaviors and neuromodulatory system genes remain largely unaffected in conditional mutants. Reductions in interneuron density were identified throughout the brain of Chd2^+/- mice, and the GABA_A positive allosteric modulator, L-838,417, was effective in treating abnormal social behavior. Our results suggest a postdevelopmental role for Chd2 in memory whereas neuropsychiatric conditions may be driven by more complex circuit mechanisms involving sexually dimorphic disruptions in brain development.