Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes.
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.
Willie
Jon T
JT
Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Chemelli
Richard M
RM
Sinton
Christopher M
CM
Tokita
Shigeru
S
Williams
S Clay
SC
Kisanuki
Yaz Y
YY
Marcus
Jacob N
JN
Lee
Charlotte
C
Elmquist
Joel K
JK
Kohlmeier
Kristi A
KA
Leonard
Christopher S
CS
Richardson
James A
JA
Hammer
Robert E
RE
Yanagisawa
Masashi
M
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
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