Chd8 mutation in oligodendrocytes alters microstructure and functional connectivity in the mouse brain
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RESEARCH
Chd8 mutation in oligodendrocytes alters microstructure and functional connectivity in the mouse brain Atsuki Kawamura1, Yoshifumi Abe2, Fumiko Seki3,4, Yuta Katayama1, Masaaki Nishiyama1, Norio Takata2, Kenji F. Tanaka2, Hideyuki Okano3 and Keiichi I. Nakayama1*
Abstract CHD8 encodes a chromatin-remodeling factor and is one of the most recurrently mutated genes in individuals with autism spectrum disorder (ASD). Although we have recently shown that mice heterozygous for Chd8 mutation manifest myelination defects and ASD-like behaviors, the detailed mechanisms underlying ASD pathogenesis have remained unclear. Here we performed diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rsfMRI) in oligodendrocyte lineage-specific Chd8 heterozygous mutant mice. DTI revealed that ablation of Chd8 specifically in oligodendrocytes of mice was associated with microstructural changes of specific brain regions including the cortex and striatum. The extent of these changes in white matter including the corpus callosum and fornix was correlated with total contact time in the reciprocal social interaction test. Analysis with rsfMRI revealed changes in functional brain connectivity in the mutant mice, and the extent of such changes in the cortex, hippocampus, and amygdala was also correlated with the change in social interaction. Our results thus suggest that changes in brain microstructure and functional connectivity induced by oligodendrocyte dysfunction might underlie altered social interaction in mice with oligodendrocyte-specific CHD8 haploinsufficiency. Keywords: Autism spectrum disorder, CHD8, Oligodendrocyte, Diffusion tensor imaging, Functional connectivity Introduction Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviors. Structural and functional alterations in the brain of individuals with ASD have been identified by magnetic resonance imaging (MRI). For example, volumetric differences in several brain regions including the cortex, striatum, amygdala, and cerebellum have been detected in such individuals [1, 2]. Diffusion tensor imaging (DTI), a specific type *Correspondence: [email protected]‑u.ac.jp 1 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3‑1‑1 Maidashi, Higashi‑ku, Fukuoka, Fukuoka 812‑8582, Japan Full list of author information is available at the end of the article
of MRI, has also revealed microstructural changes in gray and white matter that are associated with ASD [3]. Moreover, resting-state functional MRI (rsfMRI) has uncovered a complex pattern of both hypo- and hyperconnectivity across the brain of ASD patients [4, 5]. Whether the alterations detected by such imaging studies contribute to the symptoms of ASD has remained to be demonstrated, however. Mutations in the gene for chromodomain helicase DNA-binding protein 8 (CHD8) have been iden
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