Ketamine-induced sustained modulation of GABAA receptor function in mouse hippocampal neurons following anesthesia.
Anesthesiology – June 09, 2025
Source: PubMed
Summary
A single dose of ketamine during surgery may help prevent post-anesthesia memory problems. The drug works by regulating brain receptors that control inhibitory signals, particularly in the hippocampus - a key memory center. Lab tests showed ketamine prevents excessive activity of these receptors and protects both recognition and spatial memory in mice after anesthesia.
Abstract
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. 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. 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. 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.