Journal
CELLS
Volume 9, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/cells9051244
Keywords
Smpd1; acid sphingomyelinase; forebrain; depressive-like behavior; anxiety-like behavior; ceramide
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Funding
- Forschungsstiftung Medizin at the University Hospital Erlangen
- German Research Foundation DFG [SFB779 A06, 270949263/GRK2162, GU 335/29-3, KO 947/13-3]
- funding program Open Access Publishing of the Friedrich-Alexander University Erlangen-Nurnberg (FAU)
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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.
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