Characterization of a novel mouse model for CHD2-related neurodevelopmental disorder

Mutations in dozens of chromatin regulators have been implicated in neurodevelopmental disorders. One of these genes is chromodomain helicase DNA binding 2 (CHD2), encoding for a chromatin modifier with largely unknown neuronal functions. In humans, heterozygous loss of function mutations in CHD2 are associated with severe childhood-onset epilepsy, global developmental delay, intellectual disability, and autistic-like features. Here, we characterized the epileptic and behavioral phenotypes of a mouse model with Chd2 haploinsufficiency (Chd2+/m and Chd2m/m mice). Interestingly, we discovered that the genetic background dramatically affected the phenotypes. While no phenotypes were observed on the pure C57BL/6J background, backcrossing these mice onto the 129X1/SvJ genetic background gradually uncovered neurodevelopmental phenotypes. On this background, Chd2m/m were smaller, with reduced weight and length at 34 days post-natal. Moreover, Chd2+/m and Chd2m/m showed motor deficits, with clasping behavior and reduced motor learning, while Chd2m/m also showed hyperactivity in the open field. Autistic-like features were also observed, with Chd2+/m demonstrating increased repetitive-like behavior in the marble burying test and Chd2+/m and Chd2m/m showing reduced nest-building abilities. Furthermore, quantitative analysis of background electrocorticography (ECoG) activity showed a global reduction in total power in Chd2+/m and Chd2m/m mice, observed in all frequency bands up to 100 Hz. Together, these results reinforce that this Chd2 mouse model displays motor deficits, autistic-related behaviors, and abnormal neuronal activity, providing a new avenue for studying the molecular basis and treatment options for this intractable disease.