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Sustained increase in α5GABAA receptor function impairs memory after anesthesia
Agnieszka A. Zurek, … , Eric W.R. Salter, Beverley A. Orser
Agnieszka A. Zurek, … , Eric W.R. Salter, Beverley A. Orser
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(12):5437-5441. https://doi.org/10.1172/JCI76669.
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Brief Report Neuroscience Article has an altmetric score of 118

Sustained increase in α5GABAA receptor function impairs memory after anesthesia

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Abstract

Many patients who undergo general anesthesia and surgery experience cognitive dysfunction, particularly memory deficits that can persist for days to months. The mechanisms underlying this postoperative cognitive dysfunction in the adult brain remain poorly understood. Depression of brain function during anesthesia is attributed primarily to increased activity of γ-aminobutyric acid type A receptors (GABAARs), and it is assumed that once the anesthetic drug is eliminated, the activity of GABAARs rapidly returns to baseline and these receptors no longer impair memory. Here, using a murine model, we found that a single in vivo treatment with the injectable anesthetic etomidate increased a tonic inhibitory current generated by α5 subunit–containing GABAARs (α5GABAARs) and cell-surface expression of α5GABAARs for at least 1 week. The sustained increase in α5GABAAR activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of α5GABAARs completely reversed the memory deficits after anesthesia. Similarly, the inhaled anesthetic isoflurane triggered a persistent increase in tonic current and cell-surface expression of α5GABAARs. Thus, α5GABAAR function does not return to baseline after the anesthetic is eliminated, suggesting a mechanism to account for persistent memory deficits after general anesthesia.

Authors

Agnieszka A. Zurek, Jieying Yu, Dian-Shi Wang, Sean C. Haffey, Erica M. Bridgwater, Antonello Penna, Irene Lecker, Gang Lei, Tom Chang, Eric W.R. Salter, Beverley A. Orser

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Figure 3

Reversal of impairment after a sedative dose of etomidate and the effects of an anesthetizing dose of etomidate.

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Reversal of impairment after a sedative dose of etomidate and the effect...
(A–C) Effects of etomidate (8 mg/kg i.p.) on (A) memory performance in WT mice treated with L-655,708 (L6, 0.5 mg/kg, n = 6–11, 1-way ANOVA, Dunnett’s post-test), (B) memory performance in Gabra5–/– mice (n = 8–13, 1-way ANOVA, Dunnett’s post-test at each time point), and (C) plasticity at Schaffer collateral-CA1 synapses 24 hours after etomidate in Gabra5–/– slices. For all fPSP data, insets: traces recorded before (a) and 60 minutes after (b) 20-Hz stimulation. Bar graph shows summarized data for the last 5 minutes of recording (n = 7–8). (D–G) Effects of an anesthetizing dose of etomidate (20 mg/kg i.p.) in WT mice on (D) memory performance (n = 9–10), (E) plasticity (n = 6–7), (F) tonic current (n = 7–8), and (G) surface and total expression of α5 subunits (n = 4) in hippocampal slices 24 hours after etomidate. MW is shown as kDa. Data are shown as mean ± SEM. Unpaired, 2-tailed Student’s t test unless otherwise indicated. *P < 0.05; **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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