| BackgroundDepression,also called major depressive disorder(MDD),is a common mental disease,which mainly manifested as deject,lack of interest and social avoidance.Those with the most severe depression evenly accompanied by self-injury or suicidal behavior,in addition,the high incidence and recurrence rate aggravating serious burden to families and society.Although the researches on depression have made some progress in the past,the pathophysiological mechanism of depression is still unclear,and there is a lack of rapid and accurate diagnostic indicators.There are many hypotheses on etiology of depression,such as monoamine hypothesis,neurotransmitter receptor hypothesis,neurotrophic hypothesis,hypothalamic-pituitaryadrenal(HPA)axis disorder and so on.Pigment epithelial-derived factor(PEDF)is a multifunctional glycoprotein encoded by SERPINF1.Our previous study found that compared with the healthy control group,PEDF was significantly downregulated in the plasma of MDD patients in first-episode and without treatment,and up-regulated after effective antidepressant treatment.Moreover,the expression of PEDF in serum and hippocampus of two classical depression animal models,Chronic unpredictable mild stress(CUMS)and Chronic social defeat stress(CSDS),was also significantly decreased.More and more evidence showed that PEDF was related to depression.As a key brain region regulating cognition,memory and emotion,the prefrontal cortex(PFC)has been studied extensively on the pathogenesis of depression,but there are few reports on the relationship between PEDF and the PFC.Purpose1.Verify the changes of PEDF expression in plasma of MDD patients.2.Verify the expression changes of PEDF in the periphery and PFC on the depression-like animal model.3.Evaluate whether there are behavioral changes after PEDFoverexpression in the PFC of mice,then clarify the depression-related neurotransmitter changes in the PEDF-overexpression mice,thereby further exploring the mechanisms of antidepressant effect of PEDF in the PFC.Methods1.Enzyme linked Immuno-Absorbent Assay(ELISA)was used to detect the alteration of PEDF in the plasma samples from clinical MDD patients and healthy subjects.2.CSDS depression animal model was established.After behavioral assessment,ELISA and western blotting was used respectively to verify the PEDF level in the serum and PFC of CSDS mice.3.Adeno-associated virus(AAV)containing exogenous PEDF was injected into PFC of wild-type mouse by stereotaxic injection technology.The level of 28 key neurotransmitters in the PFC were detected by Liquid chromatography-coupled tandem mass spectrometry(LC-MS/MS)and then screening for differential neurotransmitters.Results1.Plasma content of PEDF in MDD patients was significantly less than the healthy control group;2.Western blotting and ELISA results showed that,comparing with the control group,the PEDF expression was significantly decreased in the PFC and a descend trend in the serum of the CSDS mice;3.The results of behavioral tests showed depression-resistant phenotypes in the PEDF overexpression group compared with the control group.Comparing the levels of neurotransmitters in the PFC of mice between the two groups and found that 5-hydroxyindoleacetic acid(5-HIAA)、Kynurenine(Kyn)、5-hydroxytryptamine(5-HT)、Ornithine(Orn)、Glutamine(Gln)were significantly up-regulated in the PEDF overexpression group,while 5-hydroxytryptophan(5-HTrp)、Glutamic acid(Glu)and Aspartic acid(Asp)were down-regulated.ConclusionOur study first reported that PEDF was decreased in the PFC of depression animal model.Mice overexpressing PEDF in the PFC showed a depression-resistant phenotype,and the metabolomic results showed that the altered neurotransmitters in the PFC were mainly focused on the tryptophan and glutamate pathways.We proposed that PEDF may exerts antidepressant effects via PFC,which is another exploration of the pathophysiological mechanisms of depression,suggesting that PEDF may be a new diagnostic and therapeutic target for MDD. |
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