ERK1/2-dependent BDNF synthesis and signaling is required for the antidepressant effect of microglia stimulation

• Published in: Brain, behavior, and immunity behavior, and immunity, 2022-11, Vol.106, p.147-160
• Main Authors: Lu, Xu, Liu, Huijun, Cai, Zixuan, Hu, Zhichao, Ye, Minxiu, Gu, Yue, Wang, Yue, Wang, Dan, Lu, Qun, Shen, Zhongxia, Shen, Xinhua, Huang, Chao
• Format: Article
• Language: English
• Subjects: BDNF; Depression; ERK1/2; Hippocampus; Microglia
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2022.08.005

•Infusion of anti-BDNF antibody into DG abolishes the antidepressant effect of LPS.•Antidepressant effects of LPS are blocked in BDNF Val66Met Knock-in mice.•Antidepressant effects of LPS are blocked by inhibition of BDNG-TrkB signaling.•The ERK1/2 signal mediates the LPS-induced synthesis of BDNF in DG.•ERK1/2 inhibition abolishes the antidepressant effect of LPS. Depressed mice have lower numbers of microglia in the dentate gyrus (DG). Reversal of this decline by a single low dose of lipopolysaccharide (LPS) may have antidepressant effects, but there is little information on the molecular mechanisms underlying this effect. It is known that impairment of brain-derived neurotrophic factor (BDNF) signaling is involved in the development of depression. Here, we used a combination of neutralizing antibodies, mutant mice, and pharmacological approaches to test the role of BDNF-tyrosine kinase receptor B (TrkB) signaling in the DG in the effect of microglial stimulation. Our results suggest that inhibition of BDNF signaling by infusion of an anti-BDNF antibody, the BDNF receptor antagonist K252a, or knock-in of the mutant BDNF Val68Met allele abolished the antidepressant effect of LPS in chronically stressed mice. Increased BDNF synthesis in DG, mediated by extracellular signal-regulated kinase1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling, was essential for the antidepressant effect of microglial stimulation. These results suggest that increased BDNF synthesis through activation of ERK1/2 caused by a single LPS injection and subsequent TrkB signaling are required for the antidepressant effect of hippocampal microglial stimulation.