Abstract
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.