The Mechanism Of Antidepressant-like Effets Of Microglia In The Status Of Alternative Activation

Depression with a heavy burden of economy and society, its pathophysiology is limited success understanding. Microglial cells are generally considered as the immune cells of the CNS. They respond to any kind of pathology with a reaction termed microglial activation. Recent study revealed the phenotype of microglial cells is the role to explore the pathological process of depression.This study examined the role of dynamic alterations in microglia activation status in the mice of chronic mild stress(CMS)-induced depressive-like condition. The chronic mild stress(CMS) animal model has been developed to mimic the development and progress of clinical depression. We report that following a period of chronic treatment with pioglitazone, a PPARγ agonist, in the mice of chronic mild stress-induced depression-like behaviors, the results showed that pioglitazone has the function of antidepressant-like effect. When some CMS-mice were treated with pioglitazone and GW9662, a PPARγ antagonist, the GW9662 significantly reversed the function of pioglitazone. The status of microglia also has been changed with the expression of inflammatory cytokines, as well as the markers of M1, M2 phenotype.Meanwhile, we cultured the microglial cell line of N9 cell, and stimulation with the lipopolysaccharide(LPS), usually resulted in severe inflammatory responses. However, one must ask whether these paradigms accurately reflect microglial functions. LPS stimulation has long been considered the gold standard for microglial activation. Then treatment with the pioglitazone and GW9662, was similar to the experimental paradigms in vivo. Nevertheless, this research continued to mechanism of microglia alteration.The results showed that pioglitazone could reverse the CMS induced microglia of classic activation, decrease the expression of M1 markers and pro-inflammatory cytokines, as well as the microglia was in the status of alternative activation. However, all of these results were reversed by GW9662. Following in vitro, LPS activated N9 cell and resulted in the high levels of pro-inflammatory cytokines, and microglia displayed increased expression of M1 activation markers as well as dystrophic morphology. Blockade of these changes was pioglitazone, while GW9662 also suppressed the subsequent microglial translation. Maybe the NF-κB is an important role in the alteration.In conclusion, alternative activated microglia has the function of antidepressant-like effects, maybe involvement in the signal pathway of NF-κB. Which provide reference for the mechanism of depression, and give a new idea for the development of antidepressant drugs.