Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability

Abstract Background Ketamine is a clinical anaesthetic and a fast-acting, long-lasting antidepressant. Ketamine is known for its antagonistic actions on N-methyl-D-aspartate (NMDA) receptors, but mechanisms leading to antidepression are not clear. The present study examined synaptic, neuronal and circuit-level loci, the duration of ketamine’s actions, and the involvement of NMDA receptors in these actions. Methods Extracellular evoked field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant (10 μM) and anaesthetic (350 μM) concentrations. Effects of NMDA receptor antagonists, DL-2-Amino-5-phosphonovaleric acid (APV) and MK-801, γ-aminobutyric acid (GABA) receptor antagonist bicuculline, and a potassium channel blocker tetraethylammonium (TEA) were also studied. Results Ketamine decreased population spike (PS) amplitudes during application, but a long-lasting increase in PS amplitudes was seen during washout of ketamine. While the acute effects of ketamine were reversed by bicuculline, the washout increase was not altered. This long-term increase was statistically significant ( p <0.01, Wilcoxon Rank Test), sustained for >2 hours, and involved postsynaptic mechanisms. A similar, long-lasting effect was produced by MK-801 but was only partially evident with APV, demonstrating the importance of channel block downstream of NMDA receptors. Furthermore, TEA produced a lasting excitability increase, indicating possible involvement of potassium channel block in ketamine’s long-term effects. Conclusions This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anaesthesia, while increased excitatory transmission contributes to its antidepressant effects. Published Abstracts Society for Neuroscience Annual Meeting 2019 Association of University Anesthesiologists Annual Meeting 2020 International Anesthesia Research Society Annual Meeting 2020 The Science of Consciousness Conference 2020 International Society for Anaesthetic Pharmacology Annual Meeting 2020 Western Anesthesia Residents Conference 2021 Association of University Anesthesiologists Annual Meeting 2021 International Anesthesia Research Society Annual Meeting 2021