Astrocyte-microglia crosstalk in the hippocampus mediates cognitive impairments induced by chronic intermittent hypoxia

  • Neurobiol Dis. 2025 Sep 22:216:107117. doi: 10.1016/j.nbd.2025.107117.
Zhen-Huan Wu  1 ,  Ming-Rui Zhai  1 ,  Yu-Rong Wang  1 ,  Long Ren  1 ,  Jie Pan  2 ,  Lei Xiao  3 ,  Yue-Hua Liu  4
Affiliations
  • 1. Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, China.
  • 2. Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 3. Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 4. Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 40992699 DOI: 10.1016/j.nbd.2025.107117
Abstract

Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a common systemic disease with a high-risk factor for developing cognitive impairment. However, the possible mechanism(s) underlying the cognitive function impairment in CIH remain largely unknown. In this study, our results reveal that 8-week CIH reliably induces significant cognitive impairment, synaptic deficits, and pronounced microglial activation characterized by excessive synaptic phagocytosis. Pharmacological depletion of microglia using PLX5622 ameliorated these CIH-induced impairments. Furthermore, CIH enhanced the interaction between activated astrocytes and microglia, accompanied by upregulation of complement C3 in astrocytes and C3aR in microglia. Notably, blocking C3aR with SB290157 attenuated microglial overactivation, reduced aberrant synaptic engulfment, and improved cognitive performance in CIH-exposed mice. Collectively, these findings demonstrate that C3/C3aR-mediated astrocyte-microglia crosstalk contributes to CIH-induced cognitive dysfunction by activating microglia to excessive phagocytosis of synapses.

Keywords
Chronic intermittent hypoxia; Cognitive impairment; Complement component; Microglia phagocytosis; Synaptic connection.
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