Involvement of Ca2+-Dependent Hyperpolarization in Sleep Duration in Mammals
Involvement of Ca2+-Dependent Hyperpolarization in Sleep Duration in Mammals
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DOI：
10.1016/j.neuron.2016.02.032
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发表时间：
2016-04-06
期刊：
影响因子：
16.2
通讯作者：
Ueda, Hiroki R.
中科院分区：
文献类型：
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作者：
Tatsuki, Fumiya;Sunagawa, Genshiro A.;Ueda, Hiroki R.
哺乳动物睡眠持续时间调节的详细分子机制仍然难以捉摸。为了解决这一挑战，我们构建了一个简单的计算模型，它概括了慢波睡眠和清醒状态的电生理特征。综合分叉分析预测，钙依赖性超极化通路可能在慢波睡眠中发挥作用，因此在睡眠持续时间的调节。为了实验验证预测，我们生成并分析了21只KO小鼠。在这里，我们发现受损的Ca 2+依赖性K+通道（Kcnn 2和Kcnn 3），电压门控Ca 2+通道（Cacna 1g和Cacna 1h）或Ca 2 +/钙调蛋白依赖性激酶（Camk 2a和Camk 2b）减少睡眠时间，而受损的质膜Ca 2 + ATP酶（Atp 2b 3）增加睡眠时间。药物干预和全脑成像证实，受损的NMDA受体减少睡眠时间，并直接增加细胞的兴奋性。基于这些结果，我们提出了一个假设，钙依赖性超极化途径的基础上调节哺乳动物的睡眠时间。
The detailed molecular mechanisms underlying the regulation of sleep duration in mammals are still elusive. To address this challenge, we constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep and awake states. Comprehensive bifurcation analysis predicted that a Ca2+-dependent hyperpolarization pathway may play a role in slow-wave sleep and hence in the regulation of sleep duration. To experimentally validate the prediction, we generate and analyze 21 KO mice. Here we found that impaired Ca2+-dependent K+ channels (Kcnn2 and Kcnn3), voltage-gated Ca2+ channels (Cacna1g and Cacna1h), or Ca2+/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca2+ ATPase (Atp2b3) increases sleep duration. Pharmacological intervention and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca2+-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals.