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Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs

Erich Gulbins, Monica Palmada, Martin Reichel, Anja Lüth, Christoph Böhmer, Davide Amato, Christian P Müller, Carsten H Tischbirek, Teja W Groemer, Ghazaleh Tabatabai, Katrin A Becker, Philipp Tripal, Sven Staedtler, Teresa F Ackermann, Johannes van Brederode, Christian Alzheimer, Michael Weller, Undine E Lang, Burkhard Kleuser, Heike Grassmé & Johannes Kornhuber
AffiliationsContributionsCorresponding authors
Nature Medicine 19, 934–938 (2013) doi:10.1038/nm.3214
Received 26 November 2012 Accepted 23 April 2013 Published online 16 June 2013
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Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.

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Author information
References• Author information• Supplementary information
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
Erich Gulbins, Monica Palmada, Christoph Böhmer, Katrin A Becker & Heike Grassmé
Department of Surgery, University of Cincinnati, Cincinnati, USA.
Erich Gulbins
Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Martin Reichel, Davide Amato, Christian P Müller, Carsten H Tischbirek, Teja W Groemer, Philipp Tripal, Sven Staedtler & Johannes Kornhuber
Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany.
Anja Lüth & Burkhard Kleuser
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Ghazaleh Tabatabai & Michael Weller
Neuroscience Center Zurich, Zurich, Switzerland.
Ghazaleh Tabatabai
Department of Physiology I, University of Tübingen, Tübingen, Germany.
Teresa F Ackermann
Institute of Physiology and Pathophysiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Johannes van Brederode & Christian Alzheimer
Department of Psychiatry and Psychotherapy, University Hospital Basel, Basel, Switzerland.
Undine E Lang
E.G. and J.K. initiated the studies, designed experiments and supervised research. E.G., J.K. and M.W. wrote the manuscript. E.G. also performed most mouse studies. E.G., K.A.B. and G.T. performed the histological studies and developed the polyclonal Asm-specific antibody. M.P. and C.B. performed the C. elegans studies. A.L. and B.K. measured ceramide concentrations by mass spectrometry. M.W. designed some experiments and participated in BrdU stainings. H.G. performed the confocal microscopy studies. J.K., P.T. and S.S. performed experiments on the concentration-dependent inhibition of ASM by antidepressant drugs. M.R. and M.P. performed experiments on 5-HT uptake in cultured hippocampal neurons. M.R. and J.K. performed experiments on 5-HT uptake in mouse brain synaptosomes. C.H.T. and T.W.G. designed and performed synapse staining and confocal analyses. T.F.A., U.E.L. and E.G. performed behavioral experiments. C.P.M., D.A., M.R. and J.K. designed and performed hippocampal injection and microdialysis studies. C.A., J.v.B., M.R. and J.K. designed and performed electrophysiological studies in hippocampal slices. All authors discussed the results and commented on the manuscript.

Competing financial interests
The authors declare no competing financial interests.

Corresponding authors
Correspondence to: Erich Gulbins or Johannes Kornhuber
Supplementary information
References• Author information• Supplementary information
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Supplementary Text and Figures (22 MB)
Supplementary Figures 1–13, Supplementary Notes 1–3 and Supplementary Methods

Additional data
The addition of internodal breeding and animals to show the correlation between reproduction and state of mind emotions and belonging in community ecosystem environment emotional stability sexual response to mating and the application of depression in men and women as related to animal models


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