Etomidate impairs long-term potentiation in vitro by targeting α5-subunit containing GABAA receptors on nonpyramidal cells

F. Clifford Rodgers, Ewa D. Zarnowska, Kurt T. Laha, Elif Engin, Anja Zeller, Ruth Keist, Uwe Rudolph, Robert A. Pearce

Research output: Contribution to journalArticlepeer-review

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 towardα5-GABAARs on nonpyramidal cells as the essential effectors controlling plasticity in this in vitro model of learning and memory.

Original languageEnglish (US)
Pages (from-to)9707-9716
Number of pages10
JournalJournal of Neuroscience
Volume35
Issue number26
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

Keywords

  • GABA receptor
  • LTP
  • Learning and memory
  • Mechanisms of anesthesia

ASJC Scopus subject areas

  • Neuroscience(all)

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