Etomidate blocks LTP and impairs learning but does not enhance tonic inhibition in mice carrying the N265M point mutation in the beta3 subunit of the GABAA receptor

NEUROPHARMACOLOGY

卷:93

Article

Zarnowska, E. D.¹  Rodgers, F. C.^1,2  Oh, I.³  Rau, V.³  Lor, C.¹  Laha, K. T.¹  Jurd, R.⁴  Rudolph, U.^4,5,6  Eger, E. I³  Pearce, R. A.¹ 

[1] Univ Wisconsin, Sch Med & Publ Hlth, Dept Anesthesiol, Madison, WI 53705 USA

[2] Univ Wisconsin, Neurosci Training Program, Madison, WI 53705 USA

[3] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA

[4] Univ Zurich, Inst Pharmacol & Toxicol, CH-8006 Zurich, Switzerland

[5] McLean Hosp, Lab Genet Neuropharmacol, Belmont, MA 02178 USA

[6] Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA USA

关键词: Hippocampus;    Tonic inhibition;    Etomidate;    LTP;    Learning;    GABA receptors;   

DOI  :  10.1016/j.neuropharm.2015.01.011

来源: Elsevier

【 摘 要 】

Enhancement of tonic inhibition mediated by extrasynaptic alpha 5-subunit containing GABA(A) receptors (GABA(A)Rs) has been proposed as the mechanism by which a variety of anesthetics, including the general anesthetic etomidate, impair learning and memory. Since alpha 5 subunits preferentially partner with beta 3 subunits, we tested the hypothesis that etomidate acts through beta 3-subunit containing GABA(A)Rs to enhance tonic inhibition, block LTP, and impair memory. We measured the effects of etomidate in wild type mice and in mice carrying a point mutation in the GABA(A)R beta 3-subunit (beta 3-N265M) that renders these receptors insensitive to etomidate. Etomidate enhanced tonic inhibition in CA1 pyramidal cells of the hippocampus in wild type but not in mutant mice, demonstrating that tonic inhibition is mediated by beta 3-subunit containing GABA(A)Rs. However, despite its inability to enhance tonic inhibition, etomidate did block LIP in brain slices from mutant mice as well as in those from wild type mice. Etomidate also impaired fear conditioning to context, with no differences between genotypes. In studies of recombinant receptors expressed in HEK293 cells, alpha 5 beta 1 gamma 2L GABA(A)Rs were insensitive to amnestic concentrations of etomidate (1 mu M and below), whereas alpha 5 beta 32 gamma 2L and alpha 5 beta 3y2L GABA(A)Rs were enhanced. We conclude that etomidate enhances tonic inhibition in pyramidal cells through its action on alpha 5 beta 3-containing GABA(A) receptors, but blocks LTP and impairs learning by other means - most likely by modulating alpha 5 beta 2-containing GABA(A) receptors. The critical anesthetic targets underlying amnesia might include other forms of inhibition imposed on pyramidal neurons (e.g. slow phasic inhibition), or inhibitory processes on non-pyramidal cells (e.g. intemeurons). (C) 2015 Elsevier Ltd. All rights reserved.

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