Involvement of Ca2+-Dependent Hyperpolarization in Sleep Duration in Mammals

• Published in: Neuron (Cambridge, Mass.) Vol. 90; no. 1; pp. 70 - 85
• Main Authors: Tatsuki, Fumiya, Sunagawa, Genshiro A., Shi, Shoi, Susaki, Etsuo A., Yukinaga, Hiroko, Perrin, Dimitri, Sumiyama, Kenta, Ukai-Tadenuma, Maki, Fujishima, Hiroshi, Ohno, Rei-ichiro, Tone, Daisuke, Ode, Koji L., Matsumoto, Katsuhiko, Ueda, Hiroki R.
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Inc 06.04.2016; Elsevier Limited
• Subjects: Electroencephalography; Homeostasis; Hybridization; Hypotheses; Mammals; Medical research; Neurons; Studies
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.02.032

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. [Display omitted] •A simple model predicts Ca2+-dependent hyperpolarization regulates sleep duration•Impaired/enhanced Ca2+-dependent hyperpolarization decreases/increases sleep duration•Impaired Ca2+-dependent hyperpolarization increases neural excitability•Impaired Ca2+/calmodulin-dependent kinases (Camk2a/Camk2b) decreases sleep duration Tatsuki et al. present that a Ca2+-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals. They predicted the hypothesis by a simple averaged-neuron model and verified it by phenotyping 21 KO mice and whole-brain imaging with pharmacological intervention.