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

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.

Anxiety and Depression Are Related to Higher Activity of Sphingolipid Metabolizing Enzymes in the Rat Brain

“…Concomitant with their highly anxious and depressive-like phenotype, HAB rats showed increased activity of ASM and NSM as well as of AC and NC in multiple brain regions associated with anxiety-and depressive-like behavior, including the lateral septum, hypothalamus, ventral hippocampus and ventral and dorsal mesencephalon. These findings extend previous reports of increased brain ASM activity in transgenic models of MDD, namely, in ASMtg [29] and ASMtg fb mice [33]. As such, increased ASM activity was previously described in the dorsal and ventral hippocampus in ASMtg mice overexpressing ASM in the whole body [29] (no other brain regions were tested in this study), whereas in ASMtg fb mice overexpressing ASM only in the forebrain [33], ASM activity was increased in multiple brain regions.…”

“…Sex-specific and brain-regional effects of ASM activity on emotional behavior were also demonstrated in conditional transgenic mice in which the overexpression of ASM was restricted to the forebrain (ASMtg fb ). In these ASMtg fb mice, males showed higher ASM activity in the frontal cortex, hippocampus, lateral septum and amygdala that resulted in a depressive-like phenotype, whereas females showed a higher ASM activity in the hypothalamus and a social anxious phenotype but not a depressive-like phenotype [33]. Despite this improved understanding of the effects of ASM and ceramide on MDD, little is known about the involvement of other sphingomyelinases and ceramidases in the pathophysiology of MDD or anxiety [34].…”

“…On the other hand, LAB rats show a low level of anxiety and depressive-like behavior when compared with HAB rats and unselected Wistar rats [37]. Given that MDD is more prevalent in women [38] and the social anxious phenotype was observed only in female ASMtg [31] and ASMtg fb mice [33], experiments were performed in female HAB and LAB rats.…”

mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment

“…Interestingly, the effect of amitriptyline was observed specifically in the dorsal hippocampus, not in the ventral hippocampus or the frontal cortex. This specificity is in line with earlier studies suggesting that the dorsal hippocampus is the most important site for the role of ASM in MDD [ 19 , 20 , 22 ]. Of note, the dorsal hippocampus is mainly involved in cognitive functions, whereas the ventral part is more related to stress, emotion, and affect.…”

“…In murine studies, dysregulation of sphingolipid metabolism is associated with depressive-like behavior. Transgenic mice overexpressing Asm (Asm-tg) exhibit increased Asm activity and increased hippocampal ceramide levels, resulting in depressive-like behavior [ 19 , 20 , 21 ]. In a more direct approach, naïve mice that receive infusions of ceramide Cer16:0 into the dorsal hippocampus develop a depressive-like phenotype [ 22 ].…”