Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action

Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action

Abstract 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 distin...

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Autores principales: Eva Lasič, Marjeta Lisjak, Anemari Horvat, Mićo Božić, Aleksandra Šakanović, Gregor Anderluh, Alexei Verkhratsky, Nina Vardjan, Jernej Jorgačevski, Matjaž Stenovec, Robert Zorec
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Publicado: Nature Portfolio 2019
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Acceso en línea:https://doaj.org/article/9d2c933be99348ce80c4952f5d5ca559
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spelling oai:doaj.org-article:9d2c933be99348ce80c4952f5d5ca5592021-12-02T15:09:45ZAstrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action10.1038/s41598-019-47459-z2045-2322https://doaj.org/article/9d2c933be99348ce80c4952f5d5ca5592019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-47459-zhttps://doaj.org/toc/2045-2322Abstract 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.Eva LasičMarjeta LisjakAnemari HorvatMićo BožićAleksandra ŠakanovićGregor AnderluhAlexei VerkhratskyNina VardjanJernej JorgačevskiMatjaž StenovecRobert ZorecNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-12 (2019)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Eva Lasič
Marjeta Lisjak
Anemari Horvat
Mićo Božić
Aleksandra Šakanović
Gregor Anderluh
Alexei Verkhratsky
Nina Vardjan
Jernej Jorgačevski
Matjaž Stenovec
Robert Zorec
Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action
description Abstract 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.
format article
author Eva Lasič
Marjeta Lisjak
Anemari Horvat
Mićo Božić
Aleksandra Šakanović
Gregor Anderluh
Alexei Verkhratsky
Nina Vardjan
Jernej Jorgačevski
Matjaž Stenovec
Robert Zorec
author_facet Eva Lasič
Marjeta Lisjak
Anemari Horvat
Mićo Božić
Aleksandra Šakanović
Gregor Anderluh
Alexei Verkhratsky
Nina Vardjan
Jernej Jorgačevski
Matjaž Stenovec
Robert Zorec
author_sort Eva Lasič
title Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action
title_short Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action
title_full Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action
title_fullStr Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action
title_full_unstemmed Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action
title_sort astrocyte specific remodeling of plasmalemmal cholesterol composition by ketamine indicates a new mechanism of antidepressant action
publisher Nature Portfolio
publishDate 2019
url https://doaj.org/article/9d2c933be99348ce80c4952f5d5ca559
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