title: 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 GABA(A) receptor.
abstract: Enhancement of tonic inhibition mediated by extrasynaptic α5-subunit containing GABAA receptors (GABAARs) has been proposed as the mechanism by which a variety of anesthetics, including the general anesthetic etomidate, impair learning and memory. Since α5 subunits preferentially partner with β3 subunits, we tested the hypothesis that etomidate acts through β3-subunit containing GABAARs 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 GABAAR β3-subunit (β3-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 β3-subunit containing GABAARs. However, despite its inability to enhance tonic inhibition, etomidate did block LTP 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, α5β1γ2L GABAARs were insensitive to amnestic concentrations of etomidate (1 μM and below), whereas α5β2γ2L and α5β3γ2L GABAARs were enhanced. We conclude that etomidate enhances tonic inhibition in pyramidal cells through its action on α5β3-containing GABAA receptors, but blocks LTP and impairs learning by other means - most likely by modulating α5β2-containing GABAA 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. interneurons).
authors: School of Medicine and Public Health, Department of Anesthesiology, Belmont.
authors: E D
authors: ED
authors: Zarnowska
authors: School of Medicine and Public Health, Department of Anesthesiology, Belmont.|Neuroscience Training Program, University of Wisconsin-Madison, Belmont.
authors: F C
authors: FC
authors: Rodgers
authors: Department of Anesthesia, University of California-San Francisco, Belmont.
authors: I
authors: I
authors: Oh
authors: Department of Anesthesia, University of California-San Francisco, Belmont.
authors: V
authors: V
authors: Rau
authors: School of Medicine and Public Health, Department of Anesthesiology, Belmont.
authors: C
authors: C
authors: Lor
authors: School of Medicine and Public Health, Department of Anesthesiology, Belmont.
authors: K T
authors: KT
authors: Laha
authors: Institute of Pharmacology and Toxicology, University of Zurich, Belmont.
authors: R
authors: R
authors: Jurd
authors: Institute of Pharmacology and Toxicology, University of Zurich, Belmont.|Laboratory of Genetic Neuropharmacology, McLean Hospital, and Department of Psychiatry, Harvard Medical School University, Belmont.
authors: U
authors: U
authors: Rudolph
authors: Department of Anesthesia, University of California-San Francisco, Belmont.
authors: E I
authors: EI
authors: Eger
authors: School of Medicine and Public Health, Department of Anesthesiology, Belmont.
authors: R A
authors: RA
authors: Pearce
mesh_terms: D000818:Animals; D003214:Conditioning, Classical / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007859:Learning Disabilities / Q000139:chemically induced* / Q000235:genetics; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects; D010852:Picrotoxin / Q000494:pharmacology; D017354:Point Mutation / Q000235:genetics*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics*
chemical_list: D005045:Etomidate; D018756:GABA Antagonists; D006993:Hypnotics and Sedatives; D010852:Picrotoxin; D011963:Receptors, GABA-A
keywords: Etomidate; GABA receptors; Hippocampus; LTP; Learning; Tonic inhibition