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.

中文翻译：

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少突胶质细胞 Chd8 突变改变小鼠大脑的微观结构和功能连接


CHD8 编码染色质重塑因子，是自闭症谱系障碍 (ASD) 患者中最常发生突变的基因之一。尽管我们最近发现 Chd8 突变杂合子小鼠表现出髓鞘形成缺陷和 ASD 样行为，但 ASD 发病机制的详细机制仍不清楚。在这里，我们对少突胶质细胞谱系特异性 Chd8 杂合突变小鼠进行了扩散张量成像 (DTI) 和静息态功能磁共振成像 (rsfMRI)。 DTI 显示，小鼠少突胶质细胞中 Chd8 的消融与包括皮质和纹状体在内的特定大脑区域的微观结构变化有关。包括胼胝体和穹窿在内的白质变化程度与交互社交互动测试中的总接触时间相关。 rsfMRI 分析揭示了突变小鼠大脑功能连接的变化，皮层、海马体和杏仁核的这种变化程度也与社交互动的变化相关。因此，我们的结果表明，少突胶质细胞功能障碍引起的大脑微结构和功能连接的变化可能是少突胶质细胞特异性CHD8单倍体不足小鼠社交互动改变的基础。