Astrocyte specific remodeling of plasmalemmal cholesterol composition by ketamine indicates a new mechanism of antidepressant action

Lasič, Eva (author), Lisjak, Marjeta (author), Horvat, Anemari (author), Božić, Mićo (author), Šakanović, Aleksandra (author), Anderluh, Gregor (author), Verkhratsky, Alexei (author), Vardjan, Nina (author), Jorgačevski, Jernej (author), Stenovec, Matjaž (author), Zorec, Robert (author)

Ketamine is an antidepressant with rapid therapeutic onset and long-lasting effect, although the underlying mechanism(s) remain unknown. Using FRET-based nanosensors we found that ketamine increases [cAMP]$_i$ in astrocytes. Membrane capacitance recordings, however, reveal fundamentally distinct mechanisms of effects of ketamine and [cAMP]$_i$ on vesicular secretion: a rise in [cAMP]$_i$ facilitated, whereas ketamine inhibited exocytosis. By directly monitoring cholesterol-rich membrane domains with a fluorescently tagged cholesterol-specific membrane binding domain (D4) of toxin perfringolysin O, we demonstrated that ketamine induced cholesterol redistribution in the plasmalemma in astrocytes, but neither in fibroblasts nor in PC 12 cells. This novel mechanism posits that ketamine affects density and distribution of cholesterol in the astrocytic plasmalemma, consequently modulating a host of processes that may contribute to ketamine's rapid antidepressant action.

• Language: English
• Keywords: astrocytes, ketamine, cholesterol
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2019
• Number of pages: 12 str.
• Numbering: Vol. 9, art. 10957
• PID: 20.500.12556/RUL-128746
• UDC: 616-092
• ISSN on article: 2045-2322
• DOI: 10.1038/s41598-019-47459-z
• COBISS.SI-ID: 34434009
• Publication date in RUL: 27.07.2021

Record is a part of a journal

• Title: Scientific reports
• Shortened title: Sci. rep.
• Publisher: Nature Publishing Group
• ISSN: 2045-2322
• COBISS.SI-ID: 18727432

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: 29.07.2019

Secondary language

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