Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 12, Pages 5437-5441Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI76669
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Funding
- Canadian Institutes of Health Research (CIHR) [38028, 79428]
- Canada Research Chair in Anesthesia
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Heart and Stroke Foundation of Canada
- NSERC
- Kirk Weber Award in Anesthesia
- Ontario Student Opportunities Trust Fund
- Sleep and Biological Rhythms Toronto Program and Becas Chile
- Savoy Foundation
- CIHR
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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.
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