Ketamine-induced sustained modulation of GABAA receptor function in mouse hippocampal neurons following anesthesia.

Abstract

Background: Excess function of GABAA receptors that generate a tonic inhibitory conductance contributes to postanesthetic cognitive impairment. Ketamine may have postoperative cognition-sparing properties; however, whether it reduces excess GABAA receptor function is unknown. This study investigated whether ketamine prevents a sustained anesthetic-triggered increase in GABAA receptor function in vitro and mitigates postanesthetic memory deficits in vivo.

Methods: 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, GABAA receptor-mediated tonic currents were recorded from neurons using whole-cell patch clamp. Expression of BDNF and its receptor TrkB was assessed by biotinylation, Western blotting, ELISA, and qPCR. Immunostaining was used to visualize α5 subunit-containing GABAA 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.

Results: Ketamine prevented the sustained increase in GABAA receptor-mediated tonic currents triggered by etomidate and sevoflurane. This effect was independent of NMDA 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 GABAA receptors. In vivo, ketamine prevented deficits in both recognition and spatial memory that occurred after sevoflurane anesthesia.

Conclusions: Ketamine prevents general anesthetic-induced sustained increase in GABAA receptor function by facilitating BDNF-TrkB signaling. This mechanism is associated with a mitigation of postanesthetic memory deficits in mice.