Selective loss of GABAB 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

88 Scopus citations

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 GABAB1 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 GABAB 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, GABAB 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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Keywords

  • Hypocretin
  • Interneuron
  • Sleep stability
  • Synaptic input

ASJC Scopus subject areas

  • General

Cite this

Matsuki, T., Nomiyama, M., Takahira, H., Hirashima, N., Kunita, S., Takahashi, S., Yagami, K. I., Kilduff, T. S., Bettler, B., Yanagisawa, M., & Sakurai, T. (2009). Selective loss of GABAB receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proceedings of the National Academy of Sciences of the United States of America, 106(11), 4459-4464. https://doi.org/10.1073/pnas.0811126106