Involvement of Ca(2+)-Dependent Hyperpolarization in Sleep Duration in Mammals

Neuron. 2016 Apr 6;90(1):70-85. doi: 10.1016/j.neuron.2016.02.032. Epub 2016 Mar 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • 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


  • Cacna1g protein, mouse
  • Cacna1h protein, mouse
  • Calcium Channels, T-Type
  • Excitatory Amino Acid Antagonists
  • Kcnn2 protein, mouse
  • Kcnn3 protein, mouse
  • Receptors, N-Methyl-D-Aspartate
  • Small-Conductance Calcium-Activated Potassium Channels
  • Dizocilpine Maleate
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Camk2a protein, mouse
  • Camk2b protein, mouse
  • Plasma Membrane Calcium-Transporting ATPases
  • Phencyclidine
  • Calcium