PDF(Pubmed)
Abstract：
Autism spectrum disorder (ASD) affects ~2% of the population in the US, and monogenic forms of ASD often result in the most severe manifestation of the disorder. Recently, SCN2A has emerged as a leading gene associated with ASD, of which abnormal sleep pattern is a common comorbidity. SCN2A encodes the voltage-gated sodium channel NaV1.2. Predominantly expressed in the brain, NaV1.2 mediates the action potential firing of neurons. Clinical studies found that a large portion of children with SCN2A deficiency have sleep disorders, which severely impact the quality of life of affected individuals and their caregivers. The underlying mechanism of sleep disturbances related to NaV1.2 deficiency, however, is not known. Using a gene-trap Scn2a-deficient mouse model (Scn2atrap), we found that Scn2a deficiency results in increased wakefulness and reduced non-rapid-eye-movement (NREM) sleep. Brain region-specific Scn2a deficiency in the suprachiasmatic nucleus (SCN) containing region, which is involved in circadian rhythms, partially recapitulates the sleep disturbance phenotypes. At the cellular level, we found that Scn2a deficiency disrupted the firing pattern of spontaneously firing neurons in the SCN region. At the molecular level, RNA-sequencing analysis revealed differentially expressed genes in the circadian entrainment pathway including core clock genes Per1 and Per2. Performing a transcriptome-based compound discovery, we identified dexanabinol (HU-211), a putative glutamate receptor modulator, that can partially reverse the sleep disturbance in mice. Overall, our study reveals possible molecular and cellular mechanisms underlying Scn2a deficiency-related sleep disturbances, which may inform the development of potential pharmacogenetic interventions for the affected individuals.
摘要：
自闭症谱系障碍（ASD）影响美国约2％的人口，单基因形式的ASD通常导致该疾病最严重的表现。最近,SCN2A已成为与ASD相关的主要基因，其中异常睡眠模式是一种常见的合并症。SCN2A编码电压门控钠通道NaV1.2。主要在大脑中表达，NaV1.2介导神经元的动作电位放电。临床研究发现，很大一部分SCN2A缺乏症儿童存在睡眠障碍，严重影响受影响的个人及其照顾者的生活质量。与NaV1.2缺乏相关的睡眠障碍的潜在机制，然而,不知道。使用基因陷阱Scn2a缺陷小鼠模型（Scn2atrap），我们发现Scn2a缺乏导致觉醒增加和非快速眼动(NREM)睡眠减少.视交叉上核（SCN）包含区域的大脑区域特异性Scn2a缺陷，这与昼夜节律有关，部分概括了睡眠障碍表型。在细胞层面,我们发现Scn2a缺乏破坏了SCN区域自发放电神经元的放电模式。在分子水平上,RNA测序分析揭示了昼夜节律夹带途径中差异表达的基因，包括核心时钟基因Per1和Per2。进行基于转录组的化合物发现，我们鉴定了右他比诺（HU-211），一种推定的谷氨酸受体调节剂，可以部分逆转小鼠的睡眠障碍。总的来说,我们的研究揭示了Scn2a缺乏相关睡眠障碍的潜在分子和细胞机制，这可能会为受影响的个体提供潜在的药物遗传学干预措施。
