QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, February 18, 2009, 29(7):2177-2187; doi:10.1523/JNEUROSCI.4997-08.2009

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zecharia, A. Y. Articles by Franks, N. P. Search for Related Content PubMed PubMed Citation Articles by Zecharia, A. Y. Articles by Franks, N. P. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB PROPOFOL

 Previous Article  |  Next Article 

Cellular/Molecular
The Involvement of Hypothalamic Sleep Pathways in General Anesthesia: Testing the Hypothesis Using the GABA_A Receptor β₃N265M Knock-In Mouse

Anna Y. Zecharia,¹ Laura E. Nelson,^1,2 Thomas C. Gent,¹ Mark Schumacher,¹ Rachel Jurd,³ Uwe Rudolph,³ Stephen G. Brickley,¹ Mervyn Maze,^1,2 and Nicholas P. Franks^1,2

¹Biophysics Section, Blackett Laboratory, ²Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College, London SW7 2AZ, United Kingdom, and ³Institute of Pharmacology and Toxicology, University of Zürich, CH-8057 Zürich, Switzerland

Correspondence should be addressed to Nicholas P. Franks, Biophysics Section, Blackett Laboratory, Imperial College, London SW7 2AZ, UK. Email: n.franks{at}imperial.ac.uk

The GABA_A receptor has been identified as the single most important target for the intravenous anesthetic propofol. How effects at this receptor are then translated into a loss of consciousness, however, remains a mystery. One possibility is that anesthetics act on natural sleep pathways. Here, we test this hypothesis by exploring the anesthetic sensitivities of GABAergic synaptic currents in three specific brain nuclei that are known to be involved in sleep. Using whole-cell electrophysiology, we have recorded GABAergic IPSCs from the tuberomammillary nucleus (TMN), the perifornical area (Pef), and the locus ceruleus (LC) in brain slices from both wild-type mice and mice that carry a specific mutation in the GABA_A receptor β₃ subunit (N265M), which greatly reduces their sensitivity to propofol, but not to the neurosteroid alphaxalone. We find that this in vivo pattern of anesthetic sensitivity is mirrored in the hypothalamic TMN and Pef nuclei, consistent with their role as direct anesthetic targets. In contrast, anesthetic sensitivity in the LC was unaffected by the β₃N265M mutation, ruling out this nucleus as a major target for propofol. In support of the hypothesis that orexinergic neurons in the Pef are involved in propofol anesthesia, we further show that these neurons are selectively inhibited by GABAergic drugs in vivo during anesthesia, and that a modulation in the activity of Pef neurons alone can affect loss of righting reflex. Overall, our results support the idea that GABAergic anesthetics such as propofol exert their effects, at least in part, by modulating hypothalamic sleep pathways.

Key words: hypothalamus; sleep; GABA_A receptor; anesthesia; histamine; synapse

---

Received Oct. 16, 2008; revised Dec. 3, 2008; accepted Jan. 8, 2009.

Correspondence should be addressed to Nicholas P. Franks, Biophysics Section, Blackett Laboratory, Imperial College, London SW7 2AZ, UK. Email: n.franks{at}imperial.ac.uk

This article has been cited by other articles:

				E. E. Icaza, X. Huang, Y. Fu, R. R. Neubig, H. A. Baghdoyan, and R. Lydic Isoflurane-Induced Changes in Righting Response and Breathing Are Modulated by RGS Proteins Anesth. Analg., November 1, 2009; 109(5): 1500 - 1505. [Abstract] [Full Text] [PDF]

				R. Abulafia, V. Zalkind, and M. Devor Cerebral Activity during the Anesthesia-Like State Induced by Mesopontine Microinjection of Pentobarbital J. Neurosci., May 27, 2009; 29(21): 7053 - 7064. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help