2. Academic Validation
  3. The immunoregulator β-glucan produces antidepressant effects through microglia-mobilized astrocytic P2Y1R-BDNF signaling in the dentate gyrus

The immunoregulator β-glucan produces antidepressant effects through microglia-mobilized astrocytic P2Y1R-BDNF signaling in the dentate gyrus

  • Int Immunopharmacol. 2025 Sep 6:165:115494. doi: 10.1016/j.intimp.2025.115494.
Rongrong Song 1,  Rongrong Yang 2,  Xu Lu 3,  Yiming Gu 3,  Fu Li 4,  Wenfeng Hu 5,  Zhuo Chen 6,  Lin Zhang 5,  Chao Huang 7,  Lijun Liu 8
Affiliations

Affiliations

  • 1 Department of Emergency and Critical Care Medicine, The Second Affiliated Hospital of Soochow University, #1055 Sanxiang Road, Suzhou 215004, Jiangsu, China; Department of Emergency and Critical Care Medicine, Tongzhou People's Hospital, #999 Jianshe Road, Nantong 226300, Jiangsu, China.
  • 2 Department of Anesthesiology, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong 226001, Jiangsu, China.
  • 3 Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
  • 4 Department of Pharmacy, Changzhou Geriatric Hospital Affiliated to Soochow University, Changzhou No. 7 People's Hospital, #288 Yanling East Road, Changzhou 213011, Jiangsu, China.
  • 5 Department of Pharmacy, Affiliated Maternal and Child Health Hospital of Nantong University, #399 Shijidadao, Nantong 226007, Jiangsu, China.
  • 6 Department of Invasive Technology, First People's Hospital of Nantong City, the Second Affiliated Hospital of Nantong University, #666 Shengli Road, Nantong 226006, Jiangsu, China.
  • 7 Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China. Electronic address: huangchao@ntu.edu.cn.
  • 8 Department of Emergency and Critical Care Medicine, The Second Affiliated Hospital of Soochow University, #1055 Sanxiang Road, Suzhou 215004, Jiangsu, China. Electronic address: lijunliusz@sina.com.
PMID: 40915186 DOI: 10.1016/j.intimp.2025.115494
Abstract

β-Glucan, a polysaccharide from Saccharomyces cerevisiae with immunomodulatory activities that may not trigger pro-inflammatory responses in microglia, has been reported to show rapid antidepressant effects in chronically stressed Animals by restoring microglial function in the dentate gyrus. However, the mechanisms underlying this effect of β-glucan are still largely unclear. Considering the importance of astrocytic purinergic 2Y1 receptors (P2Y1Rs) and brain-derived neurotrophic factor (BDNF) in the antidepressant effects of microglial stimulation, we hypothesize that β-glucan produces antidepressant effects by mobilizing astrocytic P2Y1R-triggered BDNF signaling in the hippocampus. Our results showed that a single injection of β-glucan (20 mg/kg) reversed chronic unpredictable stress (CUS)-induced depression-like behavior and decreased adenosine triphosphate (ATP) levels in the dentate gyrus of mice, which was abolished by chemogenetic inhibition of microglia. Degradation of endogenous ATP by apyrase, non-specific antagonism of purinergic receptors by suramin, specific antagonism of P2Y1Rs in the hippocampus or selective deletion of P2Y1R in astrocytes was able to abolish the antidepressant effect of β-glucan. In addition, the β-glucan-induced increase of BDNF in the dentate gyrus of CUS mice was abolished by chemogenetic inhibition of microglia, selective deletion of P2Y1Rs in astrocytes or depletion of endogenous ATP in the hippocampus. Further analysis showed that antagonism of BDNF signaling in the hippocampus abolished the antidepressant effect of β-glucan. These results suggest that ATP-triggered astrocytic P2Y1R signaling may mediate the antidepressant effect of β-glucan by promoting BDNF production in the hippocampus.

Keywords

Astrocytic P2Y1R; BDNF; Dentate gyrus; Microglia; β-Glucan.

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