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The forebrain-specific overexpression of acid sphingomyelinase induces depressive-like symptoms in mice

  • Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brainHuman and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.show moreshow less

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Metadaten
Author details:Iulia ZoicasORCiD, Fabian SchumacherORCiDGND, Burkhard KleuserORCiDGND, Martin ReichelORCiDGND, Erich GulbinsORCiDGND, Anna FejtovaORCiD, Johannes KornhuberORCiDGND, Cosima RheinORCiD
URN:urn:nbn:de:kobv:517-opus4-524368
DOI:https://doi.org/10.25932/publishup-52436
ISSN:1866-8372
Title of parent work (German):Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
Publication series (Volume number):Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe (1186)
Publication type:Postprint
Language:English
Date of first publication:2020/04/29
Publication year:2020
Publishing institution:Universität Potsdam
Release date:2021/11/02
Tag:Smpd1; acid sphingomyelinase; anxiety-like behavior; ceramide; depressive-like behavior; forebrain
Issue:5
Article number:1244
Number of pages:14
Source:Cells 2020, 9(5), 1244; https://doi.org/10.3390/cells9051244
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
DDC classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Peer review:Referiert
Publishing method:Open Access / Green Open-Access
License (German):License LogoCC-BY - Namensnennung 4.0 International
External remark:Bibliographieeintrag der Originalveröffentlichung/Quelle
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