Male-Biased Social Deficits in Chd8+/R2219* Mouse Model of Autism Linked to Hippocampal Abnormalities
Qian Zhang1,2 · Yang Qiao3 · Huixian Li1 · Jiali Zeng1 · Jingwen Chen3 · Hui Zhou3 · Yuzheng Hu2,3 · Jianhong Luo1,2,4
1 School of Brain Science and Brain Medicine, Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310013, China
2 Nanhu Brain-computer Interface Institute, Hangzhou 311100, China
3 Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou 310058, China
4 NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a 4:1 male bias, yet the biological basis for this sex difference remains poorly understood. Heterozygous mutations in the chromatin remodeler CHD8 confer high risk for ASD, with phenotypes influenced by sex and genetic background. Here, we generated Chd8+/R2219* mice carrying a CRISPR-Cas9-generated mutation orthologous to a human variant. These mice recapitulated core ASD features, including macrocephaly and autistic-like behaviors. Notably, social deficits showed a male preponderance, directly mirroring the human sex bias. Structural magnetic resonance imaging (MRI) confirmed whole-brain enlargement in mutants, with voxel-based morphometry identifying bilateral hippocampal expansion. Crucially, hippocampal volume correlated with social deficit severity exclusively in male mutants. Functional connectivity analyses revealed disrupted hippocampal networks, and connectivity patterns within socially relevant circuits predicted behavioral outcomes. Together, our findings establish this model as exhibiting pronounced sexual dimorphism and implicate aberrant hippocampal structure and connectivity as key neural correlates of male-biased social deficits.
Keywords
Autism spectrum disorder; Sexual dimorphism; CHD8; MRI; Hippocampus
