title: Etomidate Impairs Long-Term Potentiation In Vitro by Targeting α5-Subunit Containing GABAA Receptors on Nonpyramidal Cells.
abstract: Previous experiments using genetic and pharmacological manipulations have provided strong evidence that etomidate impairs synaptic plasticity and memory by modulating α5-subunit containing GABAA receptors (α5-GABAARs). Because α5-GABAARs mediate tonic inhibition (TI) in hippocampal CA1 pyramidal cells and etomidate enhances TI, etomidate enhancement of TI in pyramidal cells has been proposed as the underlying mechanism (Martin et al., 2009). Here we tested this hypothesis by selectively removing α5-GABAARs from pyramidal neurons (CA1-pyr-α5-KO) and comparing the ability of etomidate to enhance TI and block LTP in fl-α5 (WT), global-α5-KO (gl-α5-KO), and CA1-pyr-α5-KO mice. Etomidate suppressed LTP in slices from WT and CA1-pyr-α5-KO but not gl-α5-KO mice. There was a trend toward reduced TI in both gl-α5-KO and CA1-pyr-α5-KO mice, but etomidate enhanced TI to similar levels in all genotypes. The dissociation between effects of etomidate on TI and LTP in gl-α5-KO mice indicates that increased TI in pyramidal neurons is not the mechanism by which etomidate impairs LTP and memory. Rather, the ability of etomidate to block LTP in WT and CA1-pyr-α5-KO mice, but not in gl-α5-KO mice, points toward α5-GABAARs on nonpyramidal cells as the essential effectors controlling plasticity in this in vitro model of learning and memory.
authors.affiliation: Neuroscience Training Program and Department of Anesthesiology, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: F Clifford
authors.initials: FC
authors.lastname: Rodgers
authors.affiliation: Department of Anesthesiology, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Zarnowska
authors.affiliation: Department of Anesthesiology, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Kurt T
authors.initials: KT
authors.lastname: Laha
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, Massachusetts 02478, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Elif
authors.initials: E
authors.lastname: Engin
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Anja
authors.initials: A
authors.lastname: Zeller
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Keist
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, Massachusetts 02478, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.affiliation: Department of Anesthesiology, University of Wisconsin-Madison, Madison, Wisconsin 53706, rapearce@wisc.edu.
authors.forename: Robert A
authors.identifier: http://orcid.org/0000-0002-1516-6260
authors.initials: RA
authors.lastname: Pearce
mesh_terms: D000818:Animals; D001703:Biophysics; D004558:Electric Stimulation; D005045:Etomidate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D007736:Kynurenic Acid; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D005045:Etomidate; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D006993:Hypnotics and Sedatives; D007736:Kynurenic Acid; D010852:Picrotoxin; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C496250:Gabra5 protein, mouse
keywords: GABAA receptor; LTP; learning and memory; mechanisms of anesthesia