title: 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 (GABA(A)Rs), and it is assumed that once the anesthetic drug is eliminated, the activity of GABA(A)Rs 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 GABA(A)Rs (α5GABA(A)Rs) and cell-surface expression of α5GABA(A)Rs for at least 1 week. The sustained increase in α5GABA(A)R activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of α5GABA(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 α5GABA(A)Rs. Thus, α5GABA(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.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Zurek
authors.forename: Jieying
authors.initials: J
authors.lastname: Yu
authors.forename: Dian-Shi
authors.initials: DS
authors.lastname: Wang
authors.forename: Sean C
authors.initials: SC
authors.lastname: Haffey
authors.forename: Erica M
authors.initials: EM
authors.lastname: Bridgwater
authors.forename: Antonello
authors.initials: A
authors.lastname: Penna
authors.forename: Irene
authors.initials: I
authors.lastname: Lecker
authors.forename: Gang
authors.initials: G
authors.lastname: Lei
authors.forename: Tom
authors.initials: T
authors.lastname: Chang
authors.forename: Eric W R
authors.initials: EW
authors.lastname: Salter
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000768:Anesthesia, General / Q000009:adverse effects*; D018685:Anesthetics, Inhalation / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007530:Isoflurane / Q000009:adverse effects* / Q000494:pharmacology; D008569:Memory Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; C496250:Gabra5 protein, mouse; D011963:Receptors, GABA-A; D007530:Isoflurane