Ketamine-induced Sustained Modulation of γ-Aminobutyric Acid Type A Receptor Function in Mouse Hippocampal Neurons after Anesthesia.

Abstract

Excess function of γ-aminobutyric acid type A (GABA A ) receptors that generate a tonic inhibitory conductance contributes to postanesthetic cognitive impairment. Ketamine may have postoperative cognition-sparing properties; however, whether it reduces excess GABA A receptor function is unknown. This study investigated whether ketamine prevents a sustained anesthetic-triggered increase in GABA A receptor function in vitro and mitigates postanesthetic memory deficits in vivo . Murine hippocampal neurons and cortical astrocytes were cocultured and treated for 1 h with an injectable (etomidate) or an inhaled (sevoflurane) anesthetic, with or without ketamine. After 24 h, GABA A receptor-mediated tonic currents were recorded from neurons using whole cell patch clamp. Expression of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) was assessed by biotinylation, Western blotting, ELISA, and quantitative polymerase chain reaction. Immunostaining was used to visualize α5 subunit-containing GABA A receptors in neurons. In vivo , adult mice were anesthetized with sevoflurane for 2 h, with or without ketamine, and recognition and spatial memory were assessed 24 and 48 h later, respectively. Ketamine prevented the sustained increase in GABA A receptor-mediated tonic currents triggered by etomidate and sevoflurane. This effect was independent of N -methyl- d -aspartate receptor antagonism and instead was mediated by BDNF-TrkB signaling through a GSK-3β-dependent pathway. Interestingly, ketamine did not alter BDNF levels but increased cell-surface expression of TrkB receptors and thereby facilitated BDNF-TrkB signaling. Ketamine also reduced the anesthetic-induced increase in cell-surface expression of α5 subunit-containing GABA A receptors. In vivo , ketamine prevented deficits in both recognition and spatial memory that occurred after sevoflurane anesthesia. Ketamine prevents the general anesthetic-induced sustained increase in GABA A receptor function by facilitating BDNF-TrkB signaling. This mechanism is associated with a mitigation of postanesthetic memory deficits in mice.