Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes

Jon T. Willie, Richard M. Chemelli, Christopher M. Sinton, Shigeru Tokita, S. Clay Williams, Yaz Y. Kisanuki, Jacob N. Marcus, Charlotte Lee, Joel K Elmquist, Kristi A. Kohlmeier, Christopher S. Leonard, James A Richardson, Robert E Hammer, Masashi Yanagisawa

Research output: Contribution to journalArticle

475 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)715-730
Number of pages16
JournalNeuron
Volume38
Issue number5
DOIs
StatePublished - Jun 5 2003

ASJC Scopus subject areas

  • Neuroscience(all)

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    Willie, J. T., Chemelli, R. M., Sinton, C. M., Tokita, S., Williams, S. C., Kisanuki, Y. Y., Marcus, J. N., Lee, C., Elmquist, J. K., Kohlmeier, K. A., Leonard, C. S., Richardson, J. A., Hammer, R. E., & Yanagisawa, M. (2003). Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron, 38(5), 715-730. https://doi.org/10.1016/S0896-6273(03)00330-1