Involvement of Ca(2+)-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: United States 06.04.2016
• Subjects: Animals; Calcium - metabolism; Calcium Channels, T-Type - genetics; Calcium Signaling - drug effects; Calcium Signaling - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Computer Simulation; Dizocilpine Maleate - pharmacology; Electroencephalography; Electromyography; Excitatory Amino Acid Antagonists - pharmacology; Membrane Potentials - genetics; Mice; Mice, Knockout; Phencyclidine - pharmacology; Plasma Membrane Calcium-Transporting ATPases - genetics; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Sleep - drug effects; Sleep - genetics; Sleep, REM - drug effects; Sleep, REM - genetics; Small-Conductance Calcium-Activated Potassium Channels - genetics; Time Factors
• 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 Ca(2+)-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 Ca(2+)-dependent K(+) channels (Kcnn2 and Kcnn3), voltage-gated Ca(2+) channels (Cacna1g and Cacna1h), or Ca(2+)/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca(2+) 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 Ca(2+)-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals.