Sustained increase in α5GABAA receptor function impairs memory after anesthesia
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
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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Brief Report Neuroscience

Sustained increase in α5GABAA receptor function impairs memory after anesthesia

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 2

Etomidate causes a sustained increase in tonic current and cell-surface expression of α5GABAA receptors.

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Etomidate causes a sustained increase in tonic current and cell-surface ...
(A) Traces of tonic current recorded in CA1 pyramidal neurons. BIC, bicuculline (10 μM). (B–D) Tonic current in (B) WT slices 24 hours — 2 weeks after etomidate (n = 6–19, 1-way ANOVA, Dunnett’s post-test), (C) WT slices 24 hours after dexmedetomidine (n = 4–7) and (D) WT slices measured after application of L-655,708 (L6, 200 nM) 24 hours after etomidate (n = 9–12). (E) Tonic current in Gabra5–/– slices 24 hours after etomidate (n = 6–7). (F and G) Tonic current 24 hours after etomidate treatment in (F) cultured hippocampal neurons (1 μM, 1 h, n = 21), (G) neurons in microglia-neuron cocultures (1 μM, 1 h, n = 19), and (H) neurons in astrocyte-neuron cocultures (0.25 μM, 1 h, n = 6; 1 μM, 1 h, n = 10–11). Traces were obtained from astrocyte-neuron cocultures treated with 1 μM etomidate. (I) Tonic current in neurons treated with conditioned medium from etomidate-treated astrocytes (n = 19–21). (J and K) Western blots of (J) surface and (K) total expression in hippocampal slices. Separate blots for each time point (unpaired, 2-tailed Student’s t test for each time point; 24 h, n = 6; 1 wk, n = 5; 2 wk n = 3). NKA, Na+/K+ ATPase. MW is shown in kDa. Data are shown as mean ± SEM. Unpaired, 2-tailed Student’s t test unless otherwise indicated. *P < 0.05, **P < 0.01, ***P < 0.001.