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

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 [.proportional]M 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).

New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by γ-aminobutyric acid A receptors

“…[14] In hippocampal slices of these mice, etomidate did not enhance tonic inhibition, but it still blocked long-term potentiation in CA1 pyramidal cells, and it impaired fear conditioning to context. [15] These results suggest a dissociation between tonic inhibition and impairment of memory: while β3-GABA A receptors mediate enhancement of tonic inhibition, they do not mediate impairment of memory elicited by this drug. In conjunction with the observation that amnestic concentrations of etomidate enhance receptor activity at recombinant α5β2γ2- and α5β3γ2-, but not α5β1γ2-GABA A receptors,[15] the findings mean that etomidate most likely impairs memory via receptors containing the β2-subunit, although they do not rule out the possibility that etomidate may inhibit CA1 pyramidal neurons by mechanism different from tonic inhibition, e.g., slow phasic inhibition.…”

“…[15] These results suggest a dissociation between tonic inhibition and impairment of memory: while β3-GABA A receptors mediate enhancement of tonic inhibition, they do not mediate impairment of memory elicited by this drug. In conjunction with the observation that amnestic concentrations of etomidate enhance receptor activity at recombinant α5β2γ2- and α5β3γ2-, but not α5β1γ2-GABA A receptors,[15] the findings mean that etomidate most likely impairs memory via receptors containing the β2-subunit, although they do not rule out the possibility that etomidate may inhibit CA1 pyramidal neurons by mechanism different from tonic inhibition, e.g., slow phasic inhibition. Performing similar experiments with β2(N265M)-mice would unequivocally confirm the role of β2-GABA A receptors in LTP suppression and fear conditioning to context.…”

Competitive Antagonism of Anesthetic Action at the γ-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy

“…18–20 In particular, the γ-aminobutyric acid type A (GABA A ) receptor is now known to be the principle target for the hypnotic actions of propofol and etomidate, and an important target for anesthetic barbiturates. 21–25 These drugs are highly efficacious positive allosteric modulators (PAMs) of GABA A receptor function, potentiating GABA A receptor-mediated currents that are evoked by low GABA concentrations and directly activating GABA A receptors in the absence of GABA. 26–30 …”

Oxiracetam or fastigial nucleus stimulation reduces cognitive injury at high altitude

“…A recent study suggested Oxiracetam could improve long term potentiation (LTP) caused by chronic cerebral hypoperfusion (Yao et al., 2016). It is common that LTP is associated strongly with learning and memory abilities and mainly depends on binding of excitatory receptors, such as NMDA receptor, and their neurotransmitter (Lynch, 2004; Zarnowska et al., 2015). Hence, Oxiracetam may potentiate neurotransmission, impact ion fluxes, enhance LTP, and prevent cognitive impairment.…”