Schaafsma Sara M, Gagnidze Khatuna, Reyes Anny, Norstedt Natalie, Månsson Karl, Francis Kerel, Pfaff Donald W
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065
Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1383-1388. doi: 10.1073/pnas.1619312114. Epub 2017 Jan 23.
The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.
自闭症谱系障碍（ASD）发病率中的男性偏向是这类神经发育障碍最显著的特征之一。这种性别偏向的病因远未明确，但对于总体理解ASD的病因至关重要。在此，我们研究自闭症的“三次打击”（遗传负荷×环境因素×性别）理论是否有助于解释男性占主导的现象。我们发现在与接触蛋白相关蛋白样2（Cntnap2）基因的自闭症小鼠模型中，脂多糖诱导的母体免疫激活会导致特定社交反应中出现雄性特异性缺陷。这三次“打击”在出生后第3天对超声波发声有累积效应。这些“打击”在成年期对社交识别有协同影响：只有暴露于所有三次“打击”的小鼠在社交行为的这方面表现出缺陷。在同一批小鼠的大脑中，我们发现促肾上腺皮质激素释放激素受体-1（Crhr1）基因表达存在显著的三因素相互作用，具体发生在左侧海马体，同时Crhr1启动子上的组蛋白H3 N端赖氨酸4三甲基化（H3K4me3）出现表观遗传改变。虽然很可能有多种（协同）相互作用在起作用，但下丘脑-垂体-肾上腺/应激系统（如Crhr1）中基因表达的变化是其中之一。这些数据提供了原理证明，即遗传和环境因素相互作用会导致性别特异性效应，这可能有助于解释ASD发病率中的男性偏向。
