Maximilian Schiller, Gregory C Wilson, Simone Keitsch, Matthias Soddemann, Barbara Wilker, Michael J Edwards, Norbert Scherbaum, Erich Gulbins
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引用次数: 0
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.
期刊介绍:
Pflügers Archiv European Journal of Physiology publishes those results of original research that are seen as advancing the physiological sciences, especially those providing mechanistic insights into physiological functions at the molecular and cellular level, and clearly conveying a physiological message. Submissions are encouraged that deal with the evaluation of molecular and cellular mechanisms of disease, ideally resulting in translational research. Purely descriptive papers covering applied physiology or clinical papers will be excluded. Papers on methodological topics will be considered if they contribute to the development of novel tools for further investigation of (patho)physiological mechanisms.