title: An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep.
abstract: Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis.
  
  
  CONCLUSIONS
  The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets more directly related to sleep function.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, Veterans Administration Medical Center, Dallas, Texas 75216.
authors.forename: Theresa E
authors.identifier: http://orcid.org/0000-0002-8349-6077
authors.initials: TE
authors.lastname: Bjorness
authors.affiliation: Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Dale
authors.affiliation: Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mettlach
authors.affiliation: Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390.
authors.forename: Alex
authors.identifier: http://orcid.org/0000-0001-9847-0200
authors.initials: A
authors.lastname: Sonneborn
authors.affiliation: Department of Neurology, University of Rochester, Rochester, New York 14642.
authors.forename: Bogachan
authors.initials: B
authors.lastname: Sahin
authors.affiliation: Intra-Cellular Therapies, New York, New York 10032.
authors.forename: Allen A
authors.initials: AA
authors.lastname: Fienberg
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern, Dallas, Texas 75390, International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan 305-8577.
authors.forename: Masashi
authors.identifier: http://orcid.org/0000-0002-7358-4022
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, Texas 75390, and.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.affiliation: Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, Veterans Administration Medical Center, Dallas, Texas 75216, International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan 305-8577, Department of Neuroscience, University of Texas Southwestern, Dallas, Texas 75390 robertw.greene@utsouthwestern.edu.
authors.forename: Robert W
authors.identifier: http://orcid.org/0000-0003-1355-9797
authors.initials: RW
authors.lastname: Greene
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000241:Adenosine / Q000378:metabolism*; D000248:Adenosine Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism; D012890:Sleep / Q000235:genetics / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors
chemical_list: D004965:Estrogen Antagonists; D043682:Receptor, Adenosine A1; D013629:Tamoxifen; D000248:Adenosine Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000241:Adenosine
keywords: SWS; adenosine; adenosine kinase; delta power; glia; sleep