Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Nat Neurosci. 2021 May;24(5):646-657. doi: 10.1038/s41593-021-00815-7. Epub 2021 Mar 22.
Children with autism spectrum disorder often exhibit delays in achieving motor developmental milestones such as crawling, walking and speech articulation. However, little is known about the neural mechanisms underlying motor-related deficits. Here, we reveal that mice with a syntenic deletion of the chromosome 16p11.2, a common copy number variation associated with autism spectrum disorder, also exhibit delayed motor learning without showing gross motor deficits. Using in vivo two-photon imaging in awake mice, we find that layer 2/3 excitatory neurons in the motor cortex of adult male 16p11.2-deletion mice show abnormally high activity during the initial phase of learning, and the process of learning-induced spine reorganization is prolonged. Pharmacogenetic activation of locus coeruleus noradrenergic neurons was sufficient to rescue the circuit deficits and the delayed motor learning in these mice. Our results unveil an unanticipated role of noradrenergic neuromodulation in improving the delayed motor learning in 16p11.2-deletion male mice.
自闭症谱系障碍儿童在爬行、行走和言语发音等运动发育里程碑方面常常存在延迟。然而，人们对与运动相关的缺陷的神经机制知之甚少。在这里，我们揭示了具有 16p11.2 号染色体同异位缺失的小鼠（与自闭症谱系障碍相关的常见拷贝数变异）也表现出运动学习延迟，而没有明显的运动缺陷。使用清醒小鼠的体内双光子成像，我们发现成年雄性 16p11.2 缺失小鼠运动皮层的第 2/3 层兴奋性神经元在学习的初始阶段表现出异常高的活性，并且学习诱导的脊柱重组过程延长。蓝斑去甲肾上腺素能神经元的药理学遗传激活足以挽救这些小鼠的回路缺陷和运动学习延迟。我们的结果揭示了去甲肾上腺素能神经调制在改善 16p11.2 缺失雄性小鼠运动学习延迟方面的意外作用。
