Obligatory role of microglia-mobilized hippocampal CREB-BDNF signaling in the prophylactic effect of β-glucan on chronic stress-induced depression-like behaviors in mice

  • Eur J Pharmacol. 2023 Dec 22:176288. doi: 10.1016/j.ejphar.2023.176288.
Cheng Zhao  1 ,  Ruiting Shi  2 ,  Xu Lu  3 ,  Rongrong Yang  4 ,  Zhuo Chen  5 ,  Bingran Chen  3 ,  Wenfeng Hu  6 ,  Jie Ren  3 ,  Jie Peng  3 ,  Tao Zhu  3 ,  Haojie Zhu  3 ,  Chao Huang  7
Affiliations
  • 1. Department of Pharmacy, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong 226001, Jiangsu, China. Electronic address: [email protected].
  • 2. Faculty of Humanities and Social Sciences, City University of Macau, Av. Parde Tomas Pereira, Macau, Taipa, 999078, China.
  • 3. Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
  • 4. Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
  • 5. Invasive Technology Department, The Second Affiliated Hospital of Nantong University, First People's Hospital of Nantong City, #666 Shengli Road, Nantong 226006, China.
  • 6. Department of Pharmacy, Affiliated Maternal and Child Health Hospital of Nantong University, #399 Shijidadao, Nantong 226007, China.
  • 7. Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China. Electronic address: [email protected].
PMID: 38142848 DOI: 10.1016/j.ejphar.2023.176288
Abstract

Our previous studies have reported that pre-stimulation of microglia before stress stimulation is a possible strategy to prevent depression-like phenotypes; however, the molecular mechanisms underlying this effect are still unclear. Here, we used β-glucan, a polysaccharide from Saccharomyces cerevisiae with immunomodulatory activities that cannot elicit pro-inflammatory responses in microglia, to address this issue. Our results showed that a single injection of β-glucan one day before stress exposure dose-dependently prevented the depression-like behaviors triggered by chronic unpredictable stress (CUS), which peaked at 20 mg/kg and prevented the impairment of hippocampal brain-derived neurotrophic factor (BDNF) signaling, a pathological process critical for the progression of depression-like phenotypes. Inhibition of BDNF signaling by infusion of an anti-BDNF antibody into the hippocampus, knock-in of the mutant BDNF Val68Met allele, or blockade of the BDNF receptor in the hippocampus abolished the preventive effect of β-glucan on CUS-induced depression-like behaviors. Further analysis showed that cAMP-response element binding protein (CREB)-mediated increase of BDNF expression in the hippocampus was essential for the prevention of depression-like phenotypes by β-glucan. Pretreatment with minocycline or PLX3397 before β-glucan injection to suppress microglia abolished the preventive effect of β-glucan on impaired CREB-BDNF signaling in the hippocampus and depression-like behaviors in CUS mice. These results suggest that an increase in hippocampal BDNF following CREB activation triggered by β-glucan-induced microglia stimulation and subsequent TrkB signaling mediates the preventive effect of β-glucan on depression. β-Glucan may be a more suitable immunostimulant for the prevention of depression due to its inability to promote pro-inflammatory responses in microglia.

Keywords
BDNF; CREB; Microglia; Prophylactic effect; β-glucan.
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