Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 7, Pages 2177-2187Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4997-08.2009
Keywords
hypothalamus; sleep; GABA(A) receptor; anesthesia; histamine; synapse
Categories
Funding
- Medical Research Council, UK [G0501584, G9817980]
- Chelsea and Westminster Health Care National Health Service Trust [010ANA007, 010ANA008]
- Swiss National Science Foundation [3100A0-102113]
- MRC [G0501584] Funding Source: UKRI
- Medical Research Council [G0501584] Funding Source: researchfish
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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 GABAA receptor beta(3) 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 beta(3)N265M 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.
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