Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, United States of America.
PLoS One. 2019 Nov 8;14(11):e0224876. doi: 10.1371/journal.pone.0224876. eCollection 2019.
Gene-environment interactions contribute to the risk for Autism Spectrum Disorder (ASD). Among environmental factors, prenatal exposure to stress may increase the risk for ASD. To examine if there is an interaction between exposure to maternal stress and reduced dosage or loss of Shank3, wild-type (WT), heterozygous (HET) and homozygous (HOM) female mice carrying a deletion of exons four through nine of Shank3 (Shank3ex4-9) were exposed to chronic unpredictable mild stress (CUMS) from prior to conception throughout gestation. This study examined maternal care of these dams and the white matter microstructure in the brains of their adult male offspring. Overall, our findings suggest that maternal exposure to CUMS increased pup-directed care for dams of all three genotypes. Compared to WT and HET dams, HOM dams also exhibited increased maternal care behaviors with increased time spent in the nest and reduced cage exploration, regardless of exposure to CUMS. Diffusion tensor imaging showed higher mean fractional anisotropy in the hippocampal stratum radiatum of WT and HOM male offspring from dams exposed to CUMS and HOM offspring from unexposed dams, compared to WT male offspring from unexposed dams. These data support that CUMS in Shank3-mutant dams results in subtle maternal care alterations and long-lasting changes in the white matter of the hippocampus of their offspring.
基因-环境相互作用导致自闭症谱系障碍（ASD）的风险增加。在环境因素中，产前应激暴露可能会增加 ASD 的风险。为了研究母体应激暴露与 Shank3 减少剂量或缺失之间是否存在相互作用，携带 Shank3 外显子 4 到 9 缺失的野生型（WT）、杂合子（HET）和纯合子（HOM）雌性小鼠在受孕前到妊娠期全程暴露于慢性不可预测的轻度应激（CUMS）中。本研究检查了这些母鼠的母性行为以及其成年雄性后代大脑的白质微观结构。总的来说，我们的研究结果表明，母体暴露于 CUMS 增加了所有三种基因型母鼠的幼鼠定向照顾行为。与 WT 和 HET 母鼠相比，无论是否暴露于 CUMS，HOM 母鼠还表现出更多的母性行为，如在巢中停留的时间增加，以及在笼子里探索的时间减少。弥散张量成像显示，与未暴露于 CUMS 的 WT 雄性后代相比，暴露于 CUMS 的 WT 和 HOM 雄性后代的海马辐射层的平均分数各向异性更高，而来自未暴露于 CUMS 的 HOM 后代的海马辐射层的平均分数各向异性更高。这些数据支持 Shank3 突变母鼠的 CUMS 导致微妙的母性行为改变，并导致其后代海马白质的持久变化。
