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bioRxiv · 10.1101/2025.03.18.643778

Alterations in background ECoG activity and behavioral deficits in a mouse model of CHD2-related developmental delay

Mavashov, A.·Turk, S.·Sarusi, Y.·Brusel, M.·Ben Tov Perry, R.·Quinn, S.·Almog, Y.·Vilian, K.·Ulitsky, I.·Rubinstein, M.
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Abstract

Heterozygous loss of function mutations in the CHD2 gene, encoding for chromodomain helicase DNA-binding protein 2, are associated with severe childhood-onset epilepsy, global developmental delay, and autistic features. Here, we characterized the behavioral and epileptic phenotypes of a mouse model harboring a frameshift truncating mutation in the Chd2 gene (Chd2WT/m and Chd2m/m mice). Genetic background dramatically affected the phenotypes. While no phenotypes were observed on the pure C57BL/6J background, crossing these mice onto the 129X1/SvJ genetic background gradually uncovered neurodevelopmental phenotypes. Transcriptomic analysis identified Kcnj11 as a potential genetic modifier. On the 129X1/SvJ background, Chd2m/m mice demonstrated growth retardation, and both Chd2WT/m and Chd2m/m showed motor deficits, including clasping behavior and reduced abilities to balance on a rotating rod. Autistic-like features were also observed, with Chd2m/m showing reduced nest-building abilities and Chd2WT/m demonstrating increased repetitive-like behavior in the marble burying test and altered social behavior. Quantitative analysis of electrocorticographic (ECoG) recordings revealed neuronal changes consisting of a global reduction in the total power of background activity in Chd2WT/m and Chd2m/m mice, as well as increased susceptibility to seizures induced by acute administration of 4-aminopyridine. Overall, this mouse model recapitulates multiple key phenotypes observed in CHD2 patients, providing a valuable platform to study the molecular basis and treatment options for this intractable disease.

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Mavashov, A., Turk, S., Sarusi, Y., Brusel, M., Ben Tov Perry, R., Quinn, S., Almog, Y., Vilian, K., Ulitsky, I., Rubinstein, M.. 2025-03-18. Alterations in background ECoG activity and behavioral deficits in a mouse model of CHD2-related developmental delay. https://doi.org/10.1101/2025.03.18.643778

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