Wang Chenyu, Derderian Kimberly D, Hamada Elizabeth, Zhou Xujia, Nelson Andrew D, Kyoung Henry, Ahituv Nadav, Bouvier Guy, Bender Kevin J
Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Neuron. 2024 May 1;112(9):1444-1455.e5. doi: 10.1016/j.neuron.2024.01.029. Epub 2024 Feb 26.
Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify a mechanism that underlies hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss of function in the ASD risk-factor gene SCN2A. The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one's gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A-encoded Na1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in mice via a CRISPR-activator approach that increases Scn2a expression, demonstrating that evaluation of a simple reflex can be used to assess and quantify successful therapeutic intervention.
被诊断患有自闭症谱系障碍（ASD）的儿童通常表现出感觉超敏或对感觉刺激有异常强烈的反应。这种超敏反应可能会让人难以承受，导致高度的痛苦，这对该疾病的负面影响有显著的促成作用。在这里，我们确定了一种在感觉运动反射中超敏反应的潜在机制，这种反射在人类和ASD风险因素基因SCN2A功能丧失的小鼠中被发现发生了改变。小脑依赖的前庭眼反射（VOR）有助于在运动过程中保持注视，由于小脑突触可塑性的缺陷而变得超敏。颗粒细胞中SCN2A编码的Na1.2钠通道的杂合缺失损害了向浦肯野细胞的高频传递和长时程增强，这是一种对调节VOR增益很重要的突触可塑性形式。通过增加Scn2a表达的CRISPR激活方法可以挽救小鼠的VOR可塑性，这表明对一种简单反射的评估可用于评估和量化成功的治疗干预。
