Ketamine alters functional plasticity of astroglia : an implication for antidepressant effect

Stenovec, Matjaž (author)

Ketamine, a non-competitive N–methyl–D–aspartate receptor (NMDAR) antagonist, exerts a rapid, potent and long-lasting antidepressant effect, although the cellular and molecular mechanisms of this action are yet to be clarified. In addition to targeting neuronal NMDARs fundamental for synaptic transmission, ketamine also affects the function of astrocytes, the key homeostatic cells of the central nervous system that contribute to pathophysiology of major depressive disorder. Here, I review studies revealing that (sub)anesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]$_i$) in astrocytes, attenuate stimulus-evoked astrocyte calcium signaling, which regulates exocytotic secretion of gliosignaling molecules, and stabilize the vesicle fusion pore in a narrow configuration, possibly hindering cargo discharge or vesicle recycling. Next, I discuss how ketamine affects astrocyte capacity to control extracellular K$^+$ by reducing vesicular delivery of the inward rectifying potassium channel (K$_{ir}$4.1) to the plasmalemma that reduces the surface density of K$_{ir}$4.1. Modified astroglial K$^+$ buffering impacts upon neuronal firing pattern as demonstrated in lateral habenula in a rat model of depression. Finally, I highlight the discovery that ketamine rapidly redistributes cholesterol in the astrocyte plasmalemma, which may alter the flux of cholesterol to neurons. This structural modification may further modulate a host of processes that synergistically contribute to ketamine’s rapid antidepressant action.

• Language: English
• Keywords: astrocytes, ketamine, exocytosis, cAMP, endocytosis, fusion pore, K$_{ir}$4.1, vesicle mobility, cholesterol
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 17 str.
• Numbering: Vol. 11, iss. 6, art. 573
• PID: 20.500.12556/RUL-135741
• UDC: 616-092
• ISSN on article: 2075-1729
• DOI: 10.3390/life11060573
• COBISS.SI-ID: 67452931
• Publication date in RUL: 30.03.2022

Record is a part of a journal

• Title: Life
• Shortened title: Life
• Publisher: MDPI
• ISSN: 2075-1729
• COBISS.SI-ID: 519982617

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 17.06.2021

Secondary language

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