Abstract
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-tgfb) 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-tgfb mice than in female Asm-tgfb 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-tgfb 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.
Highlights
Major depressive disorder (MDD) is a severe and chronic mood disorder with a lifetime prevalence of more than 10% [1]
We assessed Smpd1 mRNA levels in male Asm-tgfb mice to confirm our breeding strategy. In both cortical and hippocampal tissues, Asm-tgfb mice showed a significant increase in Smpd1 mRNA expression in comparison with WT mice (Figure 1A, frontal cortex, t(5) = −16.7; p < 0.001; Figure 1B, hippocampus, t(6) = −6.9; p < 0.001)
16.7; p < 0.001; Figure 1B, hippocampus, t(6) = -6.9; p < 0.001). In both cortical and hippocampal tissues, male Asm-tgfb mice showed a significant increase in Smpd1
Summary
Major depressive disorder (MDD) is a severe and chronic mood disorder with a lifetime prevalence of more than 10% [1]. Key symptoms of MDD are a depressed mood and loss of interest, anhedonia, feelings of worthlessness, weight loss, and insomnia. MDD is a very common disorder, its pathogenesis is still unclear. The acid sphingomyelinase (ASM)/ceramide system was recently implicated in the pathogenesis of MDD [2]. ASM (human; murine: Asm) is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine [3].
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