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Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo

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Title: Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo
Authors: Schiller, Maximilian, Wilson, Gregory C., Keitsch, Simone, Soddemann, Matthias, Wilker, Barbara, Edwards, Michael J., Scherbaum, Norbert, Gulbins, Erich
Source: Pflugers Arch
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Neurons, Male, Depressive Disorder, Major, Medizin, Phosphatidic Acids, PC12 Cells, Hippocampus, Rats, Mice, Inbred C57BL, Mice, PC12 Cells [MeSH], Mice, Inbred C57BL [MeSH], Depressive Disorder, Major/drug therapy [MeSH], Depressive Disorder, Major/metabolism [MeSH], Phosphatidic acid, Ceramide, Neurons/drug effects [MeSH], Original Article, Phosphatidic Acids/pharmacology [MeSH], Male [MeSH], Stress, Psychological/metabolism [MeSH], Hippocampus/metabolism [MeSH], Phosphatidic Acids/metabolism [MeSH], Major depression, Autophagy, Neurons/metabolism [MeSH], Rats [MeSH], Animals [MeSH], Autophagy/drug effects [MeSH], Mice [MeSH], Gangliosides, Autophagy/physiology [MeSH], Hippocampus/drug effects [MeSH], Corticosterone/blood [MeSH], Corticosterone/pharmacology [MeSH], Animals, Corticosterone, Stress, Psychological
Description: Major depressive disorder (MDD) is a common and severe psychiatric disease, which does not only lead to variety of neuropsychiatric symptoms, but unfortunately in a relatively large proportion of cases also to suicide. The pathogenesis of MDD still requires definition. We have previously shown that ceramide is increased in the blood plasma of patients with MDD. In mouse models of MDD, which are induced by treatment with corticosterone or application of chronic unpredictable stress, increased blood plasma ceramide also increased and caused an inhibition of phospholipase D in endothelial cells of the hippocampus and reduced phosphatidic acid levels in the hippocampus. Here, we demonstrated that corticosterone treatment of PC12 cells resulted in reduced cellular autophagy, which is corrected by treatment with phosphatidic acid. In vivo, treatment of mice with corticosterone or chronic unpredictable stress also reduced autophagy in hippocampus neurons. Autophagy was normalized upon i.v. injection of phosphatidic acid in these mouse models of MDD. In an attempt to identify targets of phosphatidic acid in neurons, we demonstrated that corticosterone reduced levels of the ganglioside GM1 in PC-12 cells and the hippocampus of mice, which were normalized by treatment of cells or i.v. injection of mice with phosphatidic acid. GM1 application also normalized autophagy in cultured neurons. Phosphatidic acid and GM1 corrected stress-induced alterations in behavior, i.e., mainly anxiety and anhedonia, in experimental MDD in mice. Our data suggest that phosphatidic acid may regulate via GM1 autophagy in neurons.
Document Type: Article
Other literature type
Language: English
ISSN: 1432-2013
0031-6768
DOI: 10.1007/s00424-024-03026-8
Access URL: https://pubmed.ncbi.nlm.nih.gov/39375214
https://repository.publisso.de/resource/frl:6512490
Rights: CC BY
Accession Number: edsair.doi.dedup.....e806150f807d5cacd9b46a78c8fad048
Database: OpenAIRE
Description
Abstract:Major depressive disorder (MDD) is a common and severe psychiatric disease, which does not only lead to variety of neuropsychiatric symptoms, but unfortunately in a relatively large proportion of cases also to suicide. The pathogenesis of MDD still requires definition. We have previously shown that ceramide is increased in the blood plasma of patients with MDD. In mouse models of MDD, which are induced by treatment with corticosterone or application of chronic unpredictable stress, increased blood plasma ceramide also increased and caused an inhibition of phospholipase D in endothelial cells of the hippocampus and reduced phosphatidic acid levels in the hippocampus. Here, we demonstrated that corticosterone treatment of PC12 cells resulted in reduced cellular autophagy, which is corrected by treatment with phosphatidic acid. In vivo, treatment of mice with corticosterone or chronic unpredictable stress also reduced autophagy in hippocampus neurons. Autophagy was normalized upon i.v. injection of phosphatidic acid in these mouse models of MDD. In an attempt to identify targets of phosphatidic acid in neurons, we demonstrated that corticosterone reduced levels of the ganglioside GM1 in PC-12 cells and the hippocampus of mice, which were normalized by treatment of cells or i.v. injection of mice with phosphatidic acid. GM1 application also normalized autophagy in cultured neurons. Phosphatidic acid and GM1 corrected stress-induced alterations in behavior, i.e., mainly anxiety and anhedonia, in experimental MDD in mice. Our data suggest that phosphatidic acid may regulate via GM1 autophagy in neurons.
ISSN:14322013
00316768
DOI:10.1007/s00424-024-03026-8