Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

Taizo Matsuki, Mika Nomiyama, Hitomi Takahira, Noriko Hirashima, Satoshi Kunita, Satoru Takahashi, Ken Ichi Yagami, Thomas S. Kilduff, Bernhard Bettler, Masashi Yanagisawa, Takeshi Sakurai

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Hypothalamic neurons that contain the neuropeptide orexin (hypo- cretin) play important roles in the regulation of sleep/wake. Here we analyze the in vivo and in vitro phenotype of mice lacking the GABA B1 gene specifically in orexin neurons (oxGKO mice) and demonstrate that GABA B receptors on orexin neurons are essential in stabilizing and consolidating sleep/wake states. In oxGKO brain slices, we show that the absence of GABA B receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs because of augmented GABA A-mediated inhibition that increases the membrane conductance and shunts postsynaptic currents in these neurons. This increase in GABA A-mediated inhibitory tone is apparently the result of an orexin receptor type 1-mediated activation of local GABAergic interneurons that project back onto orexin neurons. oxGKO mice exhibit severe fragmentation of sleep/wake states during both the light and dark periods, without showing an abnormality in total sleep time or signs of cataplexy. Thus, GABA B receptors on orexin neurons are crucial in the appropriate control of the orexinergic tone through sleep/wake states, thereby stabilizing the state switching mechanisms.

Original languageEnglish (US)
Pages (from-to)4459-4464
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number11
DOIs
StatePublished - Mar 17 2009

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GABA-B Receptors
Wakefulness
Sleep
Neurons
gamma-Aminobutyric Acid
Orexin Receptors
Cataplexy
Synaptic Potentials
Sleep Deprivation
Interneurons
Neuropeptides
Phenotype
Light
Membranes
Brain

Keywords

  • Hypocretin
  • Interneuron
  • Sleep stability
  • Synaptic input

ASJC Scopus subject areas

  • General

Cite this

Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. / Matsuki, Taizo; Nomiyama, Mika; Takahira, Hitomi; Hirashima, Noriko; Kunita, Satoshi; Takahashi, Satoru; Yagami, Ken Ichi; Kilduff, Thomas S.; Bettler, Bernhard; Yanagisawa, Masashi; Sakurai, Takeshi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 11, 17.03.2009, p. 4459-4464.

Research output: Contribution to journalArticle

Matsuki, T, Nomiyama, M, Takahira, H, Hirashima, N, Kunita, S, Takahashi, S, Yagami, KI, Kilduff, TS, Bettler, B, Yanagisawa, M & Sakurai, T 2009, 'Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 11, pp. 4459-4464. https://doi.org/10.1073/pnas.0811126106
Matsuki, Taizo ; Nomiyama, Mika ; Takahira, Hitomi ; Hirashima, Noriko ; Kunita, Satoshi ; Takahashi, Satoru ; Yagami, Ken Ichi ; Kilduff, Thomas S. ; Bettler, Bernhard ; Yanagisawa, Masashi ; Sakurai, Takeshi. / Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 11. pp. 4459-4464.
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