Inhibition of α5 γ-Aminobutyric Acid Type A Receptors Restores Recognition Memory After General Anesthesia

Abstract

General anesthetics cause cognitive deficits that persist much longer than would be expected on the basis of their pharmacokinetics. The cellular mechanisms underlying these postanesthetic cognitive deficits remain unknown. γ-Aminobutyric acid type A (GABA(A)) receptors are principal targets for most anesthetics. In particular, the α5GABA(A) receptor subtype has been implicated in acute memory blockade during anesthesia and memory deficits in the early postoperative period. We first sought to determine whether working memory and short-term recognition memory are impaired after isoflurane anesthesia. The second aim of the study was to determine whether memory deficits after isoflurane can be reversed by inhibiting α5GABA(A) receptors. We also sought to determine whether the expression of α5GABA(A) receptors is necessary for the development of memory dysfunction after isoflurane. Lastly, the effect of sevoflurane on memory was studied. Wild-type and α5GABA(A) receptor null-mutant (Gabra5-/-) mice were treated with isoflurane (1.3%; 1 minimum alveolar concentration [MAC]) or sevoflurane (2.3%; 1 MAC) or vehicle gas for 1 hour. Memory performance was assessed with a novel object recognition task. Mice were trained on the recognition task either 24 hours or 72 hours after isoflurane anesthesia. Working memory and short-term memory were tested 1 minute and 1 hour after training, respectively. To determine whether inhibition of α5GABA(A) receptors reverses memory deficits, we treated a subset of mice with L-655,708 (0.35 mg/kg or 0.7 mg/kg) 23.5 hours after isoflurane and 30 minutes before behavioral training. Short-term memory was impaired in wild-type mice 24 hours after isoflurane as evidenced by a decrease in the discrimination ratio (control 0.66 ± 0.03 vs isoflurane 0.51 ± 0.03, P = 0.0005). In contrast, working memory was not impaired by isoflurane (control 0.68 ± 0.05 vs isoflurane 0.67 ± 0.04, P = 0.979). The deficit in short-term memory was fully reversed by L-655,708 (effect of isoflurane × L-655,708, F(2,102) = 3.59, P = 0.032; isoflurane 0.51 ± 0.03 vs isoflurane + L-655,708 at 0.35 mg/kg 0.67 ± 0.03, P < 0.05). By 72 hours, the deficits in short-term memory resolved spontaneously (control 0.65 ± 0.05 vs isoflurane 0.60 ± 0.04, P = 0.441). Gabra5-/- mice showed no short-term memory deficits 24 hours after isoflurane (effect of isoflurane F(1,47) = 0.375, P = 0.544). Sevoflurane also caused memory deficits 24 hours after anesthesia, as evidence by a reduction in the discrimination ratio (control 0.63 ± 0.02 vs sevoflurane 0.53 ± 0.03, P = 0.039). Inhalational anesthetics cause deficits in anterograde recognition memory. This proof-of-concept study shows that α5GABA(A) receptors are necessary for the development of postanesthetic deficits in recognition memory and that these receptors can be targeted to restore memory even after the anesthetic has been eliminated.