Chd8 mutation in oligodendrocytes alters microstructure and functional connectivity in the mouse brain
Atsuki Kawamura1, Yoshifumi Abe2, Fumiko Seki3,4
1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka, 812-8582, Japan.
Molecular Brain
|November 24, 2020
Summary
Oligodendrocyte-specific CHD8 gene mutations in mice disrupt brain structure and function, leading to social interaction deficits relevant to autism spectrum disorder (ASD). These findings highlight oligodendrocyte dysfunction in ASD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- CHD8 is a key chromatin-remodeling gene frequently mutated in autism spectrum disorder (ASD).
- Previous studies linked heterozygous Chd8 mutations in mice to myelination issues and ASD-like behaviors, but underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the detailed mechanisms of ASD pathogenesis in mice with oligodendrocyte lineage-specific Chd8 mutations.
- To explore the relationship between brain microstructure, functional connectivity, and social behaviors.
Main Methods:
- Diffusion tensor imaging (DTI) to assess white matter microstructure.
- Resting-state functional magnetic resonance imaging (rsfMRI) to analyze brain functional connectivity.
- Reciprocal social interaction tests to evaluate social behavior.
Main Results:
- Oligodendrocyte-specific Chd8 ablation caused microstructural brain changes in the cortex and striatum.
- White matter changes in the corpus callosum and fornix correlated with social interaction deficits.
- rsfMRI revealed altered functional brain connectivity in multiple regions, also correlating with social interaction changes.
Conclusions:
- Oligodendrocyte dysfunction due to Chd8 haploinsufficiency contributes to altered brain microstructure and functional connectivity.
- These neurobiological changes are associated with impaired social interaction in mice, suggesting a potential mechanism for ASD.
- Targeting oligodendrocyte dysfunction may offer therapeutic avenues for ASD.
