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

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

  • Brain Behav Immun. 2022 Nov:106:147-160. doi: 10.1016/j.bbi.2022.08.005.
Xu Lu 1,  Huijun Liu 2,  Zixuan Cai 1,  Zhichao Hu 1,  Minxiu Ye 1,  Yue Gu 1,  Yue Wang 1,  Dan Wang 1,  Qun Lu 3,  Zhongxia Shen 4,  Xinhua Shen 4,  Chao Huang 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
  • 2 Department of Pharmacy, Yancheng First Hospital, the Fourth Affiliated Hospital of Nantong University, #66 Renmin South Road, Yancheng 224006, Jiangsu, China.
  • 3 Department of Pharmacy, Nantong Third Hospital Affiliated to Nantong University, #60 Middle Qingnian Road, Nantong 226006, Jiangsu, China.
  • 4 Department of Psychosomatic and Psychiatric Diseases, Huzhou Third Municipal Hospital, the Affiliated Hospital of Huzhou University, #2088 Tiaoxi East Road, Huzhou 313000, Zhejiang, China.
  • 5 Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China. Electronic address: [email protected].
PMID: 35995236 DOI: 10.1016/j.bbi.2022.08.005
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.

Keywords

BDNF; Depression; ERK1/2; Hippocampus; Microglia.

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