GABAA receptors mediate two distinct forms of inhibition: phasic inhibition and tonic inhibition. In the hippocampus, tonic inhibition is mainly mediated by extrasynaptic α5 subunit-containing GABAA receptors, and sustained overexpression of these receptors contributes to cognitive deficits and mood disorders. Recently, ketamine, a NMDA receptor antagonist, was shown to prevent postoperative cognitive deficits and exert long-lasting antidepressant effects in patients. Given this relationship, we hypothesize that ketamine prevents a persistent increase in α5 subunit-containing GABAA receptor activity. Using whole-cell patch-clamp recordings, we show for the first time that ketamine prevents this overactivity in mouse hippocampal neurons in vitro. Furthermore, this effect is mediated by key proteins implicated in ketamine’s antidepressant actions including BDNF and GSK3β, but not by inhibition of NMDA receptors. Interestingly, ketamine acts through both neurons and astrocytes to prevent this overactivity. Our study provides a novel mechanism for the cognition-sparing and antidepressant properties of ketamine.M.Sc.2021-11-20 00:00:0
