• Corinna Mattusch, Stephan Kratzer, Martina Buerge, Matthias Kreuzer, Tatiana Engel, Claudia Kopp, Martin Biel, Verena Hammelmann, Shui-Wang Ying, Peter A Goldstein, Eberhard Kochs, Rainer Haseneder, and Gerhard Rammes.
• From the Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (C.M., S.K., M. Buerge, M.K., T.E., C.K., E.K., R.H., G.R.); Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Munich, Germany (M. Biel, V.H.); and Department of Anesthesiology, Weill Cornell Medical College, New York, New York (S.-W.Y., P.A.G.).
• Anesthesiology. 2015 May 1;122(5):1047-59.

BackgroundThe thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined.MethodsThe effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels.ResultsXenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel-mediated Ih current amplitude by 33.4 ± 12.2% (at -133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation (V1/2) from -98.8 ± 1.6 to -108.0 ± 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2 mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo.ConclusionsHere, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon.

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