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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 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.

SUBMITTER: Lasic E

PROVIDER: S-EPMC6662760 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Lasič Eva E Lisjak Marjeta M Horvat Anemari A Božić Mićo M Šakanović Aleksandra A Anderluh Gregor G Verkhratsky Alexei A Vardjan Nina N Jorgačevski Jernej J Stenovec Matjaž M Zorec Robert R

Scientific reports 20190729 1

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 cholestero ...[more]

PMID: 31358895

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Project description:BackgroundThe NMDA receptor antagonist ketamine was found to act as a fast-acting antidepressant. The effects of single treatment were reported to persist for days to weeks, even in otherwise treatment-refractory cases. Identification of the mechanisms underlying ketamine's antidepressant action may permit development of novel drugs, with similar clinical properties but lacking psychotomimetic, sedative and other side effects.MethodsWe applied whole-genome microarray profiling to analyze detailed time-course (1, 2, 4 and 8 h) of transcriptome alterations in the striatum and hippocampus following acute administration of ketamine, memantine and phencyclidine in C57BL/6 J mice. The transcriptional effects of ketamine were further analyzed using next-generation sequencing and quantitative PCR. Gene expression alterations induced by the NMDA antagonists were compared to the molecular profiles of psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids.ResultsWe identified 52 transcripts (e.g. Dusp1, Per1 and Fkbp5) with altered expression (FDR < 1 %) in response to treatment with NMDA receptor antagonists. Functional links that connect expression of the regulated genes to the MAPK, IL-6 and insulin signaling pathways were indicated. Moreover, ketamine-regulated expression of specific gene isoforms was detected (e.g. Tsc22d3, Sgk1 and Hif3a). The comparison with other psychotropic drugs revealed that the molecular effects of ketamine are most similar to memantine and phencyclidine. Clustering based on expression profiles placed the NMDA antagonists among fluoxetine, tianeptine, as well as opioids and ethanol.ConclusionsThe identified patterns of gene expression alteration in the brain provided novel molecular classification of ketamine. The transcriptional profile of ketamine reflects its multi-target pharmacological nature. The results reveal similarities between the effects of ketamine and monoaminergic antidepressants that may explain the mechanisms of its rapid antidepressant action.

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

Publications

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

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