Ketamine Action on Astrocytes Provides New Insights into Rapid Antidepressant Mechanisms

Matjaž Stenovec, Baoman Li, Alexei Verkhratsky, Robert Zorec

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

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.

Original languageEnglish
Title of host publicationAstrocytes in Psychiatric Disorders
EditorsBaoman Li, Vladimir Parpura, Alexei Verkhratsky, Caterina Scuderi
Place of PublicationCham
PublisherSpringer Cham
Pages349-365
Number of pages17
ISBN (Electronic)9783030773755
ISBN (Print)9783030773779
DOIs
Publication statusPublished - 10 Dec 2021

Publication series

NameAdvances in Neurobiology
Volume26
ISSN (Print)2190-5215
ISSN (Electronic)2190-5223

Keywords

  • astrocytes
  • cholesterol
  • endocytosis
  • excitability
  • exocytosis
  • ketamine

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