Children's Hospital Los Angeles, The Saban Research Institute, Los Angeles, California, USA.
Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Genes Brain Behav. 2024 Apr;23(2):e12892. doi: 10.1111/gbb.12892.
Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8 haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact of Chd8 haploinsufficiency on maternal-offspring interactions. While differences in maternal care as a function of Chd8 genotype have not been studied directly, a previous study showed that pup survival was reduced when reared by Chd8 heterozygous dams compared with wild-type (WT) dams, suggesting altered maternal care as a function of Chd8 genotype. Through systematic observation of the C57BL/6 strain, we first determined the impact of Chd8 haploinsufficiency in the offspring on WT maternal care frequencies across preweaning development. We next determined the impact of maternal Chd8 haploinsufficiency on pup care. Compared with litters with all WT offspring, WT dams exhibited less frequent maternal behaviors toward litters consisting of offspring with mixed Chd8 genotypes, particularly during postnatal week 1. Dam Chd8 haploinsufficiency decreased litter survival and increased active maternal care also during postnatal week 1. Determining the impact of Chd8 haploinsufficiency on early life experiences provides an important foundation for interpreting offspring outcomes and determining mechanisms that underlie heterogeneous phenotypes.
CHD8 基因突变是自闭症谱系障碍的最高遗传风险因素之一。研究表明，杂合子缺失小鼠（Chd8 haploinsufficient mice）在某些方面表现出一些类似于临床表型的特征，但在同一品系背景下的不同模型中，一些特征的一致性存在差异。研究之间的变异来源之一可能是 Chd8 杂合子缺失对母婴互动的影响。尽管 Chd8 基因型对母婴关系的影响尚未直接研究，但之前的一项研究表明，与野生型（WT）母鼠相比，由 Chd8 杂合子母鼠抚养的幼鼠存活率降低，这表明 Chd8 基因型会改变母婴关系。通过对 C57BL/6 品系的系统观察，我们首先确定了 Chd8 杂合子缺失对 WT 母鼠在整个幼年期前的幼仔的母婴关系频率的影响。接下来，我们确定了母鼠 Chd8 杂合子缺失对幼鼠护理的影响。与所有 WT 后代的窝相比，WT 母鼠对由混合 Chd8 基因型后代组成的窝表现出较少的母婴行为，特别是在产后第 1 周。母鼠 Chd8 杂合子缺失降低了窝仔存活率，并增加了产后第 1 周的主动母婴关系。确定 Chd8 杂合子缺失对早期生活经历的影响，为解释后代结果和确定导致异质表型的机制提供了重要基础。
