摘要Major depressive disorder(MDD)is a common psychiatric disorder characterized by persistent mood despondency and loss of motivation.Although numerous hypotheses have been proposed,the possible pathogenesis of MDD remains unclear.Several recent studies show that a classic transporter protein,sortilin,is closely associated with depression.In the present study,we investigated the role of sortilin in MDD using a well-established rodent model of depression.Mice were subjected to chronic unpredictable mild stress(CUMS)for 6 weeks.We showed that the expression levels of sortilin were significantly increased in the prefrontal cortex and hippocampus of CUMS mice.The depressive-like behaviors induced by CUMS were alleviated by specific knockdown of sortilin in the prefrontal cortex and hippocampus.We revealed that sortilin facilitated acid sphingomyelinase(ASM)/ceramide signaling,which activated RhoA/ROCK2 signaling,ultimately causing the transformation of dendritic spine dynamics.Specific overexpression of sortilin in the prefrontal cortex and hippocampus induced depressive-like behaviors,which was mitigated by injection of ASM inhibitor SR33557(4 μg/μL)into the prefrontal cortex and hippocampus.In conclusion,sortilin knockdown in the prefrontal cortex and hippocampus plays an important role in ameliorating depressive-like behavior induced by CUMS,which is mainly evidenced by decreasing the trafficking of ASM from the trans-Golgi network to the lysosome and reducing the ceramide levels.Our results provide a new insight into the pathology of depression,and demonstrate that sortilin may be a potential therapeutic target for MDD.