title: Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes.
abstract: Narcolepsy-cataplexy, a neurological disorder associated with the absence of hypothalamic orexin (hypocretin) neuropeptides, consists of two underlying problems: inability to maintain wakefulness and intrusion of rapid eye movement (REM) sleep into wakefulness. Here we document, using behavioral, electrophysiological, and pharmacological criteria, two distinct classes of behavioral arrests exhibited by mice deficient in orexin-mediated signaling. Both OX2R(-/-) and orexin(-/-) mice are similarly affected with behaviorally abnormal attacks of non-REM sleep ("sleep attacks") and show similar degrees of disrupted wakefulness. In contrast, OX2R(-/-) mice are only mildly affected with cataplexy-like attacks of REM sleep, whereas orexin(-/-) mice are severely affected. Absence of OX2Rs eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset. While normal regulation of wake/non-REM sleep transitions depends critically upon OX2R activation, the profound dysregulation of REM sleep control unique to the narcolepsy-cataplexy syndrome emerges from loss of signaling through both OX2R-dependent and OX2R-independent pathways.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Jon T
authors.initials: JT
authors.lastname: Willie
authors.forename: Richard M
authors.initials: RM
authors.lastname: Chemelli
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sinton
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: S Clay
authors.initials: SC
authors.lastname: Williams
authors.forename: Yaz Y
authors.initials: YY
authors.lastname: Kisanuki
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Marcus
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lee
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Kristi A
authors.initials: KA
authors.lastname: Kohlmeier
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Leonard
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001143:Arousal / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002997:Clomipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004525:Efferent Pathways / Q000378:metabolism* / Q000503:physiopathology; D004569:Electroencephalography; D004576:Electromyography; D006632:Histamine / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009290:Narcolepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009479:Neuropeptides / Q000172:deficiency* / Q000235:genetics; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000172:deficiency* / Q000235:genetics; D012890:Sleep / Q000235:genetics*; D012895:Sleep, REM / Q000235:genetics*; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D006632:Histamine; D002997:Clomipramine