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Astroglial Mechanisms of Ketamine Action Include Reduced Mobility of Kir4.1-Carrying Vesicles

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Abstract

The finding that ketamine, an anaesthetic, can elicit a rapid antidepressant effect at low doses that lasts for weeks in patients with depression is arguably a major achievement in psychiatry in the last decades. However, the mechanisms of action are unclear. The glutamatergic hypothesis of ketamine action posits that ketamine is a N-methyl-d-aspartate receptor (NMDAR) antagonist modulating downstream cytoplasmic events in neurons. In addition to targeting NMDARs in synaptic transmission, ketamine may modulate the function of astroglia, key homeostasis-providing cells in the central nervous system, also playing a role in many neurologic diseases including depression, which affects to 20% of the population globally. We first review studies on astroglia revealing that (sub)anaesthetic doses of ketamine attenuate stimulus-evoked calcium signalling, a process of astroglial cytoplasmic excitability, regulating the exocytotic release of gliosignalling molecules. Then we address how ketamine alters the fusion pore activity of secretory vesicles, and how ketamine affects extracellular glutamate and K+ homeostasis, both considered pivotal in depression. Finally, we also provide evidence indicating reduced cytoplasmic mobility of astroglial vesicles carrying the inward rectifying potassium channel (Kir4.1), which may regulate the density of Kir4.1 at the plasma membrane. These results indicate that the astroglial capacity to control extracellular K+ concentration may be altered by ketamine and thus indirectly affect the action potential firing of neurons, as is the case in lateral habenula in a rat disease model of depression. Hence, ketamine-altered functions of astroglia extend beyond neuronal NMDAR antagonism and provide a basis for its antidepressant action through glia.

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Acknowledgements

The authors acknowledge financial support from the Slovenian Research Agency (research core funding P3-310) and projects J3 6790, J3 6789, J3 7605 and J3 9266. We kindly thank Professors Serguei Skatchkov and Misty Eaton (Central University of the Caribbean) for sharing the plasmid Kir4.1-EGFP.

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  1. Celica BIOMEDICAL, Tehnološki park 24, 1000, Ljubljana, Slovenia

    Matjaž Stenovec, Samo Pirnat & Robert Zorec

  2. Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000, Ljubljana, Slovenia

    Matjaž Stenovec, Mićo Božić & Robert Zorec

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Stenovec, M., Božić, M., Pirnat, S. et al. Astroglial Mechanisms of Ketamine Action Include Reduced Mobility of Kir4.1-Carrying Vesicles. Neurochem Res 45, 109–121 (2020). https://doi.org/10.1007/s11064-019-02744-1

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