title: Changes in the composition of brain interstitial ions control the sleep-wake cycle.
abstract: Wakefulness is driven by the widespread release of neuromodulators by the ascending arousal system. Yet, it is unclear how these substances orchestrate state-dependent, global changes in neuronal activity. Here, we show that neuromodulators induce increases in the extracellular K(+) concentration ([K(+)]e) in cortical slices electrically silenced by tetrodotoxin. In vivo, arousal was linked to AMPA receptor-independent elevations of [K(+)]e concomitant with decreases in [Ca(2+)]e, [Mg(2+)]e, [H(+)]e, and the extracellular volume. Opposite, natural sleep and anesthesia reduced [K(+)]e while increasing [Ca(2+)]e, [Mg(2+)]e, and [H(+)]e as well as the extracellular volume. Local cortical activity of sleeping mice could be readily converted to the stereotypical electroencephalography pattern of wakefulness by simply imposing a change in the extracellular ion composition. Thus, extracellular ions control the state-dependent patterns of neural activity.
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Fengfei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: John
authors.initials: J
authors.lastname: O'Donnell
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Qiwu
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Kang
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Nanna
authors.initials: N
authors.lastname: Goldman
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA. Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. nedergaard@urmc.rochester.edu.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002412:Cations / Q000032:analysis / Q000378:metabolism*; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D004569:Electroencephalography; D008274:Magnesium / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D018091:Receptors, AMPA / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*
chemical_list: D002412:Cations; D018377:Neurotransmitter Agents; D018091:Receptors, AMPA; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D008274:Magnesium; D011188:Potassium; D002118:Calcium