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Selective loss of GABAB receptors in orexin/hypocretin-producing neurons results in disrupted sleep/wakefulness architecture

Takeshi Sakurai¹, Taizo Matsuki¹, Hitomi Takahira¹, Noriko Hirashima¹, Thomas Kilduff², Satoshi Kunita³, Satoru Takahashi⁴, Ken-ichi Yagami³, Bernard Bettler⁵, Masashi Yanagisawa⁶ & Mika Nomiyama⁷

Correspondence: (Login to view email address)

1. Institute of Basic Medical Sciences, University of Tsukuba, Pharmacology
2. SRI International, Neurobiology Laboratory, Biosciences Division
3. Institute of Basic Medical Sciences, University of Tsukuba, Laboratory Animal Resource Center
4. Institute of Basic Medical Sciences, University of Tsukuba, Anatomy and Embryology
5. University of Basel, Department of Physiology
6. UT Southwestern Medical Center, HHMI / Molecular Genetics
7. ERATO, JST

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Document Type:

Manuscript

Date:

Received 29 September 2007 00:53 UTC; Posted 01 October 2007

Subjects:

Neuroscience

Tags:

• orexin
• hypocretin
• GABA
• narcolepsy
• interneuron
• sleep
• wakefulness

Abstract:

We generated mice with a selective loss of GABAB receptors in orexin neurons. Orexin neurons in these GABAB1-/-(orexin) mice showed reduced responsiveness to GABAA receptor agonists due to a compensatory increase in GABAA receptor-mediated inhibition. This increased GABAA receptor-mediated inhibition of orexin neurons is due to orexin-1 receptor-mediated activation of local GABAergic interneurons. Surprisingly, orexin neurons were also less responsive to glutamate, apparently because the augmented GABAA receptor-mediated inhibition increases the membrane conductance and shunts excitatory currents. These observations indicate that absence of GABAB receptors decreases the sensitivity of orexin neurons to both excitatory and inhibitory inputs. GABAB1-/-(orexin)mice exhibited severe fragmentation of sleep/wake states during both the light and dark periods without affecting total sleep time or inducing cataplexy, indicating that GABAB receptors are crucial regulators of orexin neurons and that “fine tuning” of orexin neurons by inhibitory and excitatory inputs is important for the stability of sleep/waking states.

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This document is licensed to the public under the Creative Commons Attribution 2.5 License

How to cite this document:

Sakurai, Takeshi, Matsuki, Taizo, Takahira, Hitomi, Hirashima, Noriko, Kilduff, Thomas, Kunita, Satoshi, Takahashi, Satoru, Yagami, Ken-ichi, Bettler, Bernard, Yanagisawa, Masashi, and Nomiyama, Mika. Selective loss of GABAB receptors in orexin/hypocretin-producing neurons results in disrupted sleep/wakefulness architecture. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2007.1195.1> (2007)

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