Modulation Of Microglia Function By Dopamine And Serotonin

Microglia,the immune competent cells of the central nervous system（CNS）,normally exist in a resting state characterized by a ramified morphology,and become activated in response to brain injury,infection,and a variety of neuroinflammatory stimuli.Microglial activation can induce beneficial or deleterious phenotypes,depending on the context of activation.Beneficial phenotypes（M2）are mediated through anti-inflammatory cytokines,such as IL-4 and TGF-β.In contrast,microglia can be acutely activated by LPS or IFN-γ,and release pro-inflammatory cytokines such as IL-6 and TNF-a.The regulation of microglia is highly complex,depending on multifactorial systems,including the neurochemical milieu.Studies have shown that stimulation of receptors in response to neurotransmitters,neuropeptides,and neuromodulators affect microglial functions,including cytokine release and phagocytosis in response to injury.In this study,we compared the responsiveness of microglia in different activation stages to neurotransmitters.Activated microglia via starvation treatment apparently showed different responses to serotonin（5-HT）or dopamine（DA）.Many signaling pathways including ERK1/2 are known to be activated by 5-HT,but ERK1/2 activation was not significantly altered upon 5-HT or DA stimulation.However,we found a significant increase of the activity of p38 MAP kinase in resting,but not in activated microglia.The increase of paxillin phosphorylation at Ser⁸³ by p38 MAP kinase upon 5-HT or DA stimulation has been also observed.The activation of phagocytosis by paxillin and cofilin is suggested by the findings that phagocytosis positively correlates with the activation of both paxillin and cofilin in microglia.Phagocytosis assessed by measuring ingestion of bacteria expressing GFP by cultured microglial cells was significantly reduced in cells stimulated with dopamine.These results indicate that 5-HT or dopamine might have a direct and significant impact on phagocytic activity of microglia through the regulation of cytoskeleton in different activation stage.