Dysfunction of the Scn8a voltage-gated sodium channel alters sleep architecture, reduces diurnal corticosterone levels, and enhances spatial memory.

Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of transient depolarizing currents and play a critical role in the electrical signaling between neurons. A null mutation in the VGSC gene SCN8A, which encodes the transmembrane protein Na(v)1.6, was identified previously in a human family. Heterozygous mutation carriers displayed a range of phenotypes, including ataxia, cognitive deficits, and emotional instability. A possible role for SCN8A was also proposed in studies examining the genetic basis of attempted suicide and bipolar disorder. In addition, mice with a Scn8a loss-of-function mutation (Scn8a(med-Tg/+)) show altered anxiety and depression-like phenotypes. Because psychiatric abnormalities are often associated with altered sleep and hormonal patterns, we evaluated heterozygous Scn8a(med-jo/+) mutants for alterations in sleep-wake architecture, diurnal corticosterone levels, and behavior. Compared with their wild-type littermates, Scn8a(med-jo/+) mutants experience more non-rapid eye movement (non-REM) sleep, a chronic impairment of REM sleep generation and quantity, and a lowered and flattened diurnal rhythm of corticosterone levels. No robust differences were observed between mutants and wild-type littermates in locomotor activity or in behavioral paradigms that evaluate anxiety or depression-like phenotypes; however, Scn8a(med-jo/+) mutants did show enhanced spatial memory. This study extends the spectrum of phenotypes associated with mutations in Scn8a and suggests a novel role for altered sodium channel function in human sleep disorders.

Scn8a电压门控钠通道的功能障碍改变睡眠结构，降低昼夜皮质酮水平，并增强空间记忆。

电压门控钠通道(VGSCs)负责瞬时去极化电流的启动和传播，并在神经元之间的电信号传递中发挥关键作用。编码跨膜蛋白Na(v)1.6的VGSC基因SCN8A中的无效突变先前在一个人类家族中被发现。杂合子突变携带者表现出一系列表型，包括共济失调、认知缺陷和情绪不稳定。在研究自杀未遂和双相情感障碍的遗传基础时，也提出了SCN8A的可能作用。此外，具有Scn8a功能缺失突变(Scn8a(med-Tg/+))的小鼠表现出改变的焦虑和抑郁样表型。因为精神异常通常与睡眠和激素模式改变有关，我们评估了杂合Scn8a(med-jo/+)突变体在睡眠-觉醒结构、昼夜皮质酮水平和行为方面的改变。与野生型同窝出生的小鼠相比，Scn8a(med-jo/+)突变体经历了更多的非快速眼动(非REM)睡眠，REM睡眠产生和数量的慢性损害，以及皮质酮水平的降低和平坦的昼夜节律。在运动活动或评估焦虑或抑郁样表型的行为范式中，突变体和野生型同窝出生者之间没有观察到显著差异；然而，Scn8a(med-jo/+)突变体确实表现出增强的空间记忆。这项研究扩展了与Scn8a突变相关的表型谱，并提出了钠通道功能改变在人类睡眠障碍中的新作用。