Astrocytes in rapid ketamine antidepressant action

Stenovec, Matjaž (author), Li, Baoman (author), Verkhratsky, Alexei (author), Zorec, Robert (author)

Ketamine, a general anaesthetic and psychotomimetic drug, exerts rapid, potent and long-lasting antidepressant effect, albeit the cellular and molecular mechanisms of this action are yet to be discovered. Besides targeting neuronal NMDARs fundamental for synaptic transmission, ketamine affects the function of astroglia the key homeostatic cells of the central nervous system that contribute to pathophysiology of psychiatric diseases including depression. Here we review studies revealing that (sub)anaesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]$_i$) in astrocytes, attenuate stimulus-evoked astrocyte calcium signalling, which regulates exocytotic secretion of gliosignalling molecules, and stabilize the vesicle fusion pore in a narrow configuration possibly hindering cargo discharge or vesicle recycling. Next we discuss how ketamine affects astroglial capacity to control extracellular K$^+$ by reducing cytoplasmic mobility of vesicles delivering the inward rectifying potassium channel (Kir4.1) to the plasmalemma. Modified astroglial K$^+$ buffering impacts upon neuronal excitability as demonstrated in the lateral habenula rat model of depression. Finally, we highlight the recent discovery that ketamine rapidly redistributes cholesterol in the plasmalemma of astrocytes, but not in fibroblasts nor in neuronal cells. This alteration of membrane structure may modulate a host of processes that synergistically contribute to ketamine's rapid and prominent antidepressant action.

• Language: English
• Keywords: astroglia, ketamine, exocytosis, cytosolic excitability, potassium homeostasis, cholesterol
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 14 str.
• Numbering: Vol. 173, art. 108158
• PID: 20.500.12556/RUL-137800
• UDC: 616-092
• ISSN on article: 1873-7064
• DOI: 10.1016/j.neuropharm.2020.108158
• COBISS.SI-ID: 17655811
• Publication date in RUL: 01.07.2022

Record is a part of a journal

• Title: Neuropharmacology
• Publisher: Elsevier
• ISSN: 1873-7064
• COBISS.SI-ID: 23233541

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: astroglia, ketamin, eksocitoza