Sustained increase in alpha 5GABA(A) receptor function impairs memory after anesthesia

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

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 gamma-aminobutyric acid type A receptors (GABA(A)Rs), 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 alpha 5 subunit-containing GABA(A)Rs (alpha 5GABA(A)Rs) and cell-surface expression of alpha 5GABA(A)Rs for at least 1 week. The sustained increase in alpha 5GABA(A)R activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of alpha 5GABA(A)Rs completely reversed the memory deficits after anesthesia. Similarly, the inhaled anesthetic isoflurane triggered a persistent increase in tonic current and cell-surface expression of alpha 5GABA(A)Rs. Thus, alpha 5GABA(A)R function does not return to baseline after the anesthetic is eliminated, suggesting a mechanism to account for persistent memory deficits after general anesthesia.

Más información

Título según WOS: ID WOS:000345677200032 Not found in local WOS DB
Título de la Revista: JOURNAL OF CLINICAL INVESTIGATION
Volumen: 124
Número: 12
Editorial: AMER SOC CLINICAL INVESTIGATION INC
Fecha de publicación: 2014
Página de inicio: 5437
Página final: 5441
DOI:

10.1172/JCI76669

Notas: ISI