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

Summary

Ketamine prevented anesthetic-triggered, sustained increases in tonic GABAA currents through facilitation of BDNF–TrkB signaling (via GSK-3β), independent of NMDA receptor antagonism. It reduced α5-GABAA surface expression and mitigated recognition and spatial memory deficits after sevoflurane in mice.

Key Findings

• Ketamine prevented sustained increases in tonic GABAA currents induced by etomidate and sevoflurane.
• Protection was mediated by BDNF–TrkB signaling via a GSK-3β-dependent pathway, independent of NMDA antagonism.
• Ketamine increased cell-surface TrkB without changing BDNF levels and reduced α5-GABAA receptor surface expression.
• In vivo, ketamine prevented recognition and spatial memory deficits after sevoflurane anesthesia.

Clinical Implications

These findings support mechanistically informed trials testing ketamine as an adjunct to reduce postanesthetic cognitive deficits, and suggest targeting BDNF–TrkB signaling or α5-GABAA receptors as therapeutic avenues.

Limitations

• Preclinical mouse and cell models limit direct clinical extrapolation
• Short-term outcomes; dosing and timing relative to clinical anesthesia require validation

Future Directions

Conduct randomized clinical trials to test ketamine’s cognitive-sparing effect and evaluate pharmacologic targeting of TrkB or α5-GABAA receptors in humans.