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GABAA receptors involved in sleep and anaesthesia: β1- versus β3-containing assemblies

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Abstract

The histaminergic neurons of the posterior hypothalamus (tuberomamillary nucleus—TMN) control wakefulness, and their silencing through activation of GABAA receptors (GABAAR) induces sleep and is thought to mediate sedation under propofol anaesthesia. We have previously shown that the β1 subunit preferring fragrant dioxane derivatives (FDD) are highly potent modulators of GABAAR in TMN neurons. In recombinant receptors containing the β3N265M subunit, FDD action is abolished and GABA potency is reduced. Using rat, wild-type and β3N265M mice, FDD and propofol, we explored the relative contributions of β1- and β3-containing GABAAR to synaptic transmission from the GABAergic sleep-on ventrolateral preoptic area neurons to TMN. In β3N265M mice, GABA potency remained unchanged in TMN neurons, but it was decreased in cultured posterior hypothalamic neurons with impaired modulation of GABAAR by propofol. Spontaneous and evoked GABAergic synaptic currents (IPSC) showed β1-type pharmacology, with the same effects achieved by 3 μM propofol and 10 μM PI24513. Propofol and the FDD PI24513 suppressed neuronal firing in the majority of neurons at 5 and 100 μM, and in all cells at 10 and 250 μM, respectively. FDD given systemically in mice induced sedation but not anaesthesia. Propofol-induced currents were abolished (1–6 μM) or significantly reduced (12 μM) in β3N265M mice, whereas gating and modulation of GABAAR by PI24513 as well as modulation by propofol were unchanged. In conclusion, β1-containing (FDD-sensitive) GABAAR represent the major receptor pool in TMN neurons responding to GABA, while β3-containing (FDD-insensitive) receptors are gated by low micromolar doses of propofol. Thus, sleep and anaesthesia depend on different GABAAR types.

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References

  1. Bonin RP, Orser BA (2008) GABA(A) receptor subtypes underlying general anesthesia. Pharmacol Biochem Behav 90:105–112

    Article  PubMed  CAS  Google Scholar 

  2. Cheng VY, Martin LJ, Elliott EM, Kim JH, Mount HT, Taverna FA, Roder JC, MacDonald JF, Bhambri A, Collinson N, Wafford KA, Orser BA (2006) Alpha5GABAA receptors mediate the amnestic but not sedative–hypnotic effects of the general anesthetic etomidate. J Neurosci 26:3713–3720

    Article  PubMed  CAS  Google Scholar 

  3. DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A, Fanselow MS, Delgado-Escueta A, Ellison GD, Olsen RW (1998) Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 18:8505–8514

    PubMed  CAS  Google Scholar 

  4. Franks NP (2008) General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 9:370–386

    Article  PubMed  CAS  Google Scholar 

  5. Friederich P, Urban BW (1999) Interaction of intravenous anesthetics with human neuronal potassium currents in relation to clinical concentrations. Anesthesiology 91:1853–1860

    Article  PubMed  CAS  Google Scholar 

  6. Gallopin T, Fort P, Eggermann E, Cauli B, Luppi PH, Rossier J, Audinat E, Muhlethaler M, Serafin M (2000) Identification of sleep-promoting neurons in vitro. Nature 404:992–995

    Article  PubMed  CAS  Google Scholar 

  7. Glykys J, Mody I (2006) Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-deficient mice. J Neurophysiol 95:2796–2807

    Article  PubMed  CAS  Google Scholar 

  8. Haas H, Panula P (2003) The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4:121–130

    Article  PubMed  CAS  Google Scholar 

  9. Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88:1183–1241

    Article  PubMed  CAS  Google Scholar 

  10. Higuchi H, Funahashi M, Miyawaki T, Mitoh Y, Kohjitani A, Shimada M, Matsuo R (2003) Suppression of the hyperpolarization-activated inward current contributes to the inhibitory actions of propofol on rat CA1 and CA3 pyramidal neurons. Neurosci Res 45:459–472

    Article  PubMed  CAS  Google Scholar 

  11. Hill-Venning C, Belelli D, Peters JA, Lambert JJ (1997) Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor. Br J Pharmacol 120:749–756

    Article  PubMed  CAS  Google Scholar 

  12. Jones PJ, Wang Y, Smith MD, Hargus NJ, Eidam HS, White HS, Kapur J, Brown ML, Patel MK (2007) Hydroxyamide analogs of propofol exhibit state-dependent block of sodium channels in hippocampal neurons: implications for anticonvulsant activity. J Pharmacol Exp Ther 320:828–836

    Article  PubMed  CAS  Google Scholar 

  13. Ju YH, Guzzo A, Chiu MW, Taylor P, Moran MF, Gurd JW, MacDonald JF, Orser BA (2009) Distinct properties of murine alpha 5 gamma-aminobutyric acid type a receptors revealed by biochemical fractionation and mass spectroscopy. J Neurosci Res 87:1737–1747

    Article  PubMed  CAS  Google Scholar 

  14. Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Vogt KE, Ledermann B, Antkowiak B, Rudolph U (2003) General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 17:250–252

    PubMed  CAS  Google Scholar 

  15. Krasowski MD, O'Shea SM, Rick CE, Whiting PJ, Hadingham KL, Czajkowski C, Harrison NL (1997) Alpha subunit isoform influences GABA(A) receptor modulation by propofol. Neuropharmacology 36:941–949

    Article  PubMed  CAS  Google Scholar 

  16. Lam DW, Reynolds JN (1998) Modulatory and direct effects of propofol on recombinant GABAA receptors expressed in xenopus oocytes: influence of alpha- and gamma2-subunits. Brain Res 784:179–187

    Article  PubMed  CAS  Google Scholar 

  17. Lin JS, Anaclet C, Sergeeva OA, Haas HL (2011) The waking brain: an update. Cell Mol Life Sci [Epub ahead of print]

  18. Lin JS, Sakai K, Vanni-Mercier G, Jouvet M (1989) A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats. Brain Res 479:225–240

    Article  PubMed  CAS  Google Scholar 

  19. Lingamaneni R, Hemmings HC Jr (2003) Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na+ channels, Ca2+ channels, and GABA(A) receptors. Br J Anaesth 90:199–211

    Article  PubMed  CAS  Google Scholar 

  20. McGinty D, Gong H, Suntsova N, Alam MN, Methippara M, Guzman-Marin R, Szymusiak R (2004) Sleep-promoting functions of the hypothalamic median preoptic nucleus: inhibition of arousal systems. Arch Ital Biol 142:501–509

    PubMed  CAS  Google Scholar 

  21. Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M (2002) The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci 5:979–984

    Article  PubMed  CAS  Google Scholar 

  22. Nguyen HT, Li KY, daGraca RL, Delphin E, Xiong M, Ye JH (2009) Behavior and cellular evidence for propofol-induced hypnosis involving brain glycine receptors. Anesthesiology 110:326–332

    PubMed  CAS  Google Scholar 

  23. Nitz D, Siegel JM (1996) GABA release in posterior hypothalamus across sleep–wake cycle. Am J Physiol 271:R1707–R1712

    PubMed  CAS  Google Scholar 

  24. Parmentier R, Kolbaev S, Klyuch BP, Vandael D, Lin JS, Selbach O, Haas HL, Sergeeva OA (2009) Excitation of histaminergic tuberomamillary neurons by thyrotropin-releasing hormone. J Neurosci 29:4471–4483

    Article  PubMed  CAS  Google Scholar 

  25. Rehberg B, Duch DS (1999) Suppression of central nervous system sodium channels by propofol. Anesthesiology 91:512–520

    Article  PubMed  CAS  Google Scholar 

  26. Reynolds DS, Rosahl TW, Cirone J, O'Meara GF, Haythornthwaite A, Newman RJ, Myers J, Sur C, Howell O, Rutter AR, Atack J, Macaulay AJ, Hadingham KL, Hutson PH, Belelli D, Lambert JJ, Dawson GR, McKernan R, Whiting PJ, Wafford KA (2003) Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms. J Neurosci 23:8608–8617

    PubMed  CAS  Google Scholar 

  27. Rudolph U, Antkowiak B (2004) Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 5:709–720

    Article  PubMed  CAS  Google Scholar 

  28. Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796–800

    Article  PubMed  CAS  Google Scholar 

  29. Sergeeva OA, Andreeva N, Garret M, Scherer A, Haas HL (2005) Pharmacological properties of GABAA receptors in rat hypothalamic neurons expressing the epsilon-subunit. J Neurosci 25:88–95

    Article  PubMed  CAS  Google Scholar 

  30. Sergeeva OA, Eriksson KS, Sharonova IN, Vorobjev VS, Haas HL (2002) GABA(A) receptor heterogeneity in histaminergic neurons. Eur J Neurosci 16:1472–1482

    Article  PubMed  Google Scholar 

  31. Sergeeva OA, Kletke O, Kragler A, Poppek A, Fleischer W, Schubring SR, Gorg B, Haas HL, Zhu XR, Lubbert H, Gisselmann G, Hatt H (2010) Fragrant dioxane derivatives identify {beta}1-subunit-containing GABAA receptors. J Biol Chem 285:23985–23993

    Article  PubMed  CAS  Google Scholar 

  32. Sherin JE, Elmquist JK, Torrealba F, Saper CB (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 18:4705–4721

    PubMed  CAS  Google Scholar 

  33. Siegwart R, Jurd R, Rudolph U (2002) Molecular determinants for the action of general anesthetics at recombinant alpha(2)beta(3)gamma(2)gamma-aminobutyric acid(A) receptors. J Neurochem 80:140–148

    Article  PubMed  CAS  Google Scholar 

  34. Steininger TL, Alam MN, Gong H, Szymusiak R, McGinty D (1999) Sleep–waking discharge of neurons in the posterior lateral hypothalamus of the albino rat. Brain Res 840:138–147

    Article  PubMed  CAS  Google Scholar 

  35. Steininger TL, Gong H, McGinty D, Szymusiak R (2001) Subregional organization of preoptic area/anterior hypothalamic projections to arousal-related monoaminergic cell groups. J Comp Neurol 429:638–653

    Article  PubMed  CAS  Google Scholar 

  36. Sukhotinsky I, Zalkind V, Lu J, Hopkins DA, Saper CB, Devor M (2007) Neural pathways associated with loss of consciousness caused by intracerebral microinjection of GABA A-active anesthetics. Eur J Neurosci 25:1417–1436

    Article  PubMed  CAS  Google Scholar 

  37. Szymusiak R, McGinty D (2008) Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 1129:275–286

    Article  PubMed  CAS  Google Scholar 

  38. Takahashi K, Lin JS, Sakai K (2006) Neuronal activity of histaminergic tuberomammillary neurons during wake–sleep states in the mouse. J Neurosci 26:10292–10298

    Article  PubMed  CAS  Google Scholar 

  39. Vanni-Mercier G, Gigout S, Debilly G, Lin JS (2003) Waking selective neurons in the posterior hypothalamus and their response to histamine H3-receptor ligands: an electrophysiological study in freely moving cats. Behav Brain Res 144:227–241

    Article  PubMed  CAS  Google Scholar 

  40. Vorobjev VS (1991) Vibrodissociation of sliced mammalian nervous tissue. J Neurosci Methods 38:145–150

    Article  PubMed  CAS  Google Scholar 

  41. Yanovsky Y, Li S, Klyuch BP, Yao Q, Blandina P, Passani MB, Lin JS, Haas H, Sergeeva OA (2011) L-Dopa activates histaminergic neurons. J Physiol 589:1349–66

    Article  PubMed  CAS  Google Scholar 

  42. Zecharia AY, Nelson LE, Gent TC, Schumacher M, Jurd R, Rudolph U, Brickley SG, Maze M, Franks NP (2009) The involvement of hypothalamic sleep pathways in general anesthesia: testing the hypothesis using the GABAA receptor beta3N265M knock-in mouse. J Neurosci 29:2177–2187

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Supported by Deutsche Forschungsgemeinschaft SFB 575/3 and 8 and a Heisenberg stipend to OAS. We are grateful to B. Görg for the help with confocal microscopy.

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Authors and Affiliations

  1. Molecular Neurophysiology, Heinrich Heine University, 40001, Düsseldorf, Germany

    Yevgenij Yanovsky, Stephan Schubring, Wiebke Fleischer, Helmut L. Haas & Olga A. Sergeeva

  2. Lehrstuhl für Zellphysiologie, Ruhr-Universität, 44780, Bochum, Germany

    Günter Gisselmann & Hanns Hatt

  3. Lehrstuhl für Tierphysiologie, Ruhr-Universität, 44780, Bochum, Germany

    Xin-Ran Zhu & Hermann Lübbert

  4. Laboratory of Genetic Neuropharmacology, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, MA, 02478, USA

    Uwe Rudolph

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  1. Yevgenij Yanovsky
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Correspondence to Olga A. Sergeeva.

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This article is published as part of the Special Issue on Sleep.

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Yanovsky, Y., Schubring, S., Fleischer, W. et al. GABAA receptors involved in sleep and anaesthesia: β1- versus β3-containing assemblies. Pflugers Arch - Eur J Physiol 463, 187–199 (2012). https://doi.org/10.1007/s00424-011-0988-4

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