Abstract
Recent studies indicate that disturbed structure and function of microglia can cause depression and associated neurogenesis impairments. Our previous work has demonstrated that exogenous fibroblast growth factor 2 (FGF2) reverses the depressive-like behaviors and the impaired hippocampal neurogenesis in a neuroinflammatory model of depression. However, whether and how the antidepressant effects of FGF2 involve the modulation of microglia activation has not been elucidated. In this study, to examine the effects of FGF2 on microglia activation, exogenous FGF2 was supplemented to the lateral ventricle of rats during the neuroinflammatory state induced by central lipopolysaccharides (LPS) administrations. It was found that FGF2 infusions reversed the LPS-induced depressive-like behaviors and inhibited the hippocampal microglia activation. In LPS-treated rats, FGF2 decreased the level of pro-inflammatory cytokines including interlukin-1β (IL-1β), IL-6 and tumor necrosis factor (TNF)-α, increased the level of IL-10, the anti-inflammatory cytokine and reversed the decreased expression of CX3CL1, a chemokine mainly expressed by neurons and keeping microglia in surveillance. Further, we examined the effects of inhibited FGF2 signaling by administration of SU5402, an FGFR inhibitor. It was found that SU5402 itself evoked depressive-like behaviors, induced microglia activation, increased production of pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α, and decreased the expression of CX3CL1. Two lines of results that FGF2 signaling and FGFR inhibitor can effectively but oppositely modulate the regulation of microglia and the generation of depressive-like behavior, suggesting that microglia-regulated mechanisms may underlie the antidepressant role of FGF2. The present data provide novel insights into the understanding of mechanism of neuroinflammation-associated depression and may serve as a novel mechanism-based target for the treatment of inflammation-related depression.
Highlights
Neuroinflammation, the inflammation of the central nervous system (CNS), is considered as a fundamental process of many pathologic conditions in the brain, such as Alzheimer’s disease and major depressive disorder (Hurley and Tizabi, 2013; Morales et al, 2014)
A post hoc analysis showed that fibroblast growth factor 2 (FGF2) reversed the decreased saccharin preference in the LPS-treated rats (p < 0.05), indicating that the neuroinflammation-induced anhedonia was ameliorated by FGF2 infusions
There were no differences in total liquid intake among groups, indicating that the physical function of drinking was not changed after LPS and FGF2 infusions
Summary
Neuroinflammation, the inflammation of the central nervous system (CNS), is considered as a fundamental process of many pathologic conditions in the brain, such as Alzheimer’s disease and major depressive disorder (Hurley and Tizabi, 2013; Morales et al, 2014). In the healthy CNS, microglia have highly ramified morphology with thin processes, which dynamically monitor the neural cell microenvironment for surveillance in efforts to maintain homeostasis (Nimmerjahn et al, 2005). Using different PET ligands, increased activated microglia were found in the prefrontal cortex (PFC) and hippocampus of depressive and bipolar disorder patients (Haarman et al, 2014; Setiawan et al, 2015). Chronic stress, which is causally related to the development of depression, could alter the number, morphology and functioning of microglia in hippocampus and PFC (Tynan et al, 2010; Hinwood et al, 2012; Pan et al, 2014; de Pablos et al, 2014). The microglial inhibitory drug minocycline was found to prevent the development of depressive-like symptoms in lipopolysaccharides (LPS) model of depression, and to ameliorate neurogenic defects and depressive-like behaviors in interferon-α model of depression (Henry et al, 2008; Zheng et al, 2015)
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