The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

Cells

卷:9

Erich Gulbins¹  Johannes Kornhuber²  Cosima Rhein²  Anna Fejtova²  Iulia Zoicas²  Martin Reichel²  Burkhard Kleuser³  Fabian Schumacher³ 

[1] Department of Molecular Biology, University of Duisburg-Essen, 45147 Essen, Germany;

[2] Department of Psychiatry and Psychotherapy, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany;

[3] Department of Toxicology, University of Potsdam, 14558 Nuthetal , Germany;

关键词: Smpd1;    acid sphingomyelinase;    forebrain;    depressive-like behavior;    anxiety-like behavior;    ceramide;   

DOI  :  10.3390/cells9051244

来源: DOAJ

【 摘 要 】

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 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.

【 授权许可】

Unknown