Hippocampal PPAR? Is A New Antidepressant Target

Purpose This study explored the role of hippocampal PPAR? in not only the pathophysiology of depression,but also the antidepessant mechanims of fluoxetine,showing that hippocampal PPAR? can be a new antidepressant target.Methods C57BL/6J mice were used to perform the chronic social defeat stress(CSDS)model of depression.Western blot and immunofluorescence experiments were done to examine the change of central PPAR? after CSDS stress.Gene-overexpressing technology,behavioral assay and western blot method were used to explore whether hippocampal PPAR? could be a new antidepressant target.By using the PPAR? antagonist MK886,behavioral assay,western blot and immunofluorescence methods,we studied whether hippocampal PPAR? is required for the antidepressant effects of fluoxetine(a antidepressant in clinical).Results Chronic CSDS stress significantly decreased the expression of hippocampal PPAR?,while hippocampal PPAR? overexpression produced robust antidepressant-like effects in the forced swim test(FST),tail suspension test(TST)and CSDS model of depression.Hippocampal PPAR? overexpression also restored the CSDS-induced decrease in hippocampal brain derived neurotrophic factor(BDNF)expression.It was also found that fluoxetine could reverse the CSDS-induced decrease of hippocampal PPAR?,while the usage of PPAR? antagonist MK886 fully blocked the antidepressant effects of fluoxetine in the FST,TST and CSDS model.Conclusions 1.Hippocampal PPAR? is involved in the pathophysiology of depression.2.Hippocampal PPAR? is a antidepressant target,as enhancing it leads to antidepressant effects.3.Hippocampal PPAR? is required for the antidepressant effects of fluoxetine.