Abstract
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Video-Audio Media
MeSH terms
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Animals
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Calcium / metabolism*
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Calcium Channels, T-Type / genetics
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Calcium Signaling / drug effects
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Calcium Signaling / genetics*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Computer Simulation
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Dizocilpine Maleate / pharmacology
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Electroencephalography
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Electromyography
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Excitatory Amino Acid Antagonists / pharmacology
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Membrane Potentials / genetics
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Mice
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Mice, Knockout
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Phencyclidine / pharmacology
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Plasma Membrane Calcium-Transporting ATPases / genetics
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Sleep / drug effects
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Sleep / genetics*
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Sleep, REM / drug effects
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Sleep, REM / genetics
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Small-Conductance Calcium-Activated Potassium Channels / genetics
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Time Factors
Substances
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Cacna1g protein, mouse
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Cacna1h protein, mouse
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Calcium Channels, T-Type
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Excitatory Amino Acid Antagonists
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Kcnn2 protein, mouse
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Kcnn3 protein, mouse
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Receptors, N-Methyl-D-Aspartate
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Small-Conductance Calcium-Activated Potassium Channels
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Dizocilpine Maleate
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Camk2a protein, mouse
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Camk2b protein, mouse
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Plasma Membrane Calcium-Transporting ATPases
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Phencyclidine
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Calcium