title: EphA4 is Involved in Sleep Regulation but Not in the Electrophysiological Response to Sleep Deprivation.
abstract: OBJECTIVE
  Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements.
  
  
  METHODS
  EphA4 knockout (KO) mice, Clock(Δ19/Δ19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day.
  
  
  RESULTS
  EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E-boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice.
  
  
  CONCLUSIONS
  Our results suggest that EphA4 is involved in circadian sleep regulation.
authors.affiliation: Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.|Department of Neuroscience, Université de Montréal, Montreal, QC, Canada.
authors.forename: Marlène
authors.initials: M
authors.lastname: Freyburger
authors.affiliation: Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Pierre
authors.affiliation: Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paquette
authors.affiliation: Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.
authors.forename: Erika
authors.initials: E
authors.lastname: Bélanger-Nelson
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bedont
authors.affiliation: Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.|Department of Psychology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Gaudreault
authors.affiliation: Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Drolet
authors.affiliation: Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Laforest
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cermakian
authors.affiliation: Department of Neuroscience, Université de Montréal, Montreal, QC, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Doucet
authors.affiliation: Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.|Department of Neuroscience, Université de Montréal, Montreal, QC, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Mongrain
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D003624:Darkness; D000069280:Electrocorticography; D055724:Electrophysiological Phenomena; D006706:Homeostasis; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D036122:Receptor, EphA4 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012890:Sleep / Q000235:genetics / Q000502:physiology*; D012892:Sleep Deprivation / Q000235:genetics / Q000503:physiopathology*; D012895:Sleep, REM / Q000235:genetics / Q000502:physiology; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism; D013997:Time Factors; D014851:Wakefulness / Q000235:genetics / Q000502:physiology
chemical_list: D056926:CLOCK Proteins; C538944:Clock protein, mouse; D036122:Receptor, EphA4
keywords: delta activity; gene expression; rapid eye movement sleep; sigma activity; suprachiasmatic nuclei