Children's Hospital Los Angeles, The Saban Research Institute, Los Angeles, CA 90027, USA; Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Children's Hospital Los Angeles, The Saban Research Institute, Los Angeles, CA 90027, USA; Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Neuron. 2023 Feb 15;111(4):539-556.e5. doi: 10.1016/j.neuron.2023.01.009. Epub 2023 Feb 3.
Preclinical models of neurodevelopmental disorders typically use single inbred mouse strains, which fail to capture the genetic diversity and symptom heterogeneity that is common clinically. We tested whether modeling genetic background diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, CHD8. We measured clinically relevant phenotypes in >1,000 mice from 33 strains, including brain and body weights and cognition, activity, anxiety, and social behaviors, using 5 behavioral assays: cued fear conditioning, open field tests in dark and bright light, direct social interaction, and social dominance. Trait disruptions mimicked those seen clinically, with robust strain and sex differences. Some strains exhibited large effect-size trait disruptions, sometimes in opposite directions, and-remarkably-others expressed resilience. Therefore, systematically introducing genetic diversity into models of neurodevelopmental disorders provides a better framework for discovering individual differences in symptom etiologies.
神经发育障碍的临床前模型通常使用单一近交系小鼠品系，这些品系无法捕捉到临床上常见的遗传多样性和症状异质性。我们测试了在小鼠遗传参考面板中模拟遗传背景多样性是否能重现对高可信度自闭症风险基因 CHD8 综合征突变的反应中的群体和个体差异。我们使用 5 种行为测定法，在 33 个品系的 1000 多只小鼠中测量了临床相关的表型，包括大脑和体重以及认知、活动、焦虑和社交行为：条件性恐惧、黑暗和明亮光线下的旷场测试、直接社交互动和社会支配地位。特征破坏模仿了临床上所见的特征，具有强大的品系和性别差异。一些品系表现出大的特征破坏效应，有时方向相反，而且——值得注意的是——其他品系表现出恢复力。因此，系统地将遗传多样性引入神经发育障碍模型为发现症状病因的个体差异提供了一个更好的框架。
