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Ketamine Action on Astrocytes Provides New Insights into Rapid Antidepressant Mechanisms

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Astrocytes in Psychiatric Disorders

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 26))

Abstract

Ketamine, a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist, exerts rapid, potent and long-lasting antidepressant effect already after a single administration of a low dose into depressed individuals. Apart from targeting neuronal NMDARs essential for synaptic transmission, ketamine also interacts with astrocytes, the principal homoeostatic cells of the central nervous system. The cellular mechanisms underlying astrocyte-based rapid antidepressant effect are incompletely understood. Here we overview recent data that describe ketamine-dependent changes in astrocyte cytosolic cAMP activity ([cAMP]i) and ketamine-induced modifications of stimulus-evoked Ca2+ signalling. The latter regulates exocytotic release of gliosignalling molecules and stabilizes the vesicle fusion pore in a narrow configuration that obstructs cargo discharge or vesicle membrane recycling. Ketamine also instigates rapid redistribution of cholesterol in the astrocyte plasmalemma that may alter flux of cholesterol to neurones, where it is required for changes in synaptic plasticity. Finally, ketamine attenuates mobility of vesicles carrying the inward rectifying potassium channel (Kir4.1) and reduces the surface density of Kir4.1 channels that control extracellular K+ concentration, which tunes the pattern of action potential firing in neurones of lateral habenula as demonstrated in a rat model of depression. Thus, diverse, but not mutually exclusive, mechanisms act synergistically to evoke changes in synaptic plasticity leading to sustained strengthening of excitatory synapses necessary for rapid antidepressant effect of ketamine.

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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.

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Authors and Affiliations

  1. Celica BIOMEDICAL, Ljubljana, Slovenia

    Matjaž Stenovec, Alexei Verkhratsky & Robert Zorec

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

    Matjaž Stenovec & Robert Zorec

  3. Practical Teaching Centre, School of Forensic Medicine, China Medical University, Shenyang, China

    Baoman Li

  4. Department of Poison Analysis, School of Forensic Medicine, China Medical University, Shenyang, China

    Baoman Li

  5. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Alexei Verkhratsky

  6. Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain

    Alexei Verkhratsky

Authors
  1. Matjaž Stenovec
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  2. Baoman Li
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  3. Alexei Verkhratsky
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  4. Robert Zorec
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Corresponding author

Correspondence to Robert Zorec .

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Editors and Affiliations

  1. Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China

    Baoman Li

  2. Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA

    Vladimir Parpura

  3. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Alexei Verkhratsky

  4. Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Rome, Italy

    Caterina Scuderi

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Stenovec, M., Li, B., Verkhratsky, A., Zorec, R. (2021). Ketamine Action on Astrocytes Provides New Insights into Rapid Antidepressant Mechanisms. In: Li, B., Parpura, V., Verkhratsky, A., Scuderi, C. (eds) Astrocytes in Psychiatric Disorders. Advances in Neurobiology, vol 26. Springer, Cham. https://doi.org/10.1007/978-3-030-77375-5_14

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