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Background <p>High-altitude hypoxia is known to impair cognition, yet the underlying cellular and molecular mechanisms remain insufficiently understood. The hippocampus, especially the dentate gyrus (DG), is highly sensitive to hypoxic stress, but the pathways driving neuronal vulnerability and glial state transitions remain unclear.</p> Methods <p>We combined human cohort cognitive assessments, hypobaric chamber mouse models, and multi-omics profiling, including single-cell and spatial transcriptomics, spatial metabolomics, and cell–cell communication analyses, to construct an integrated map of hippocampal remodeling under hypoxia. Mechanistic validation was performed through IL1α knockdown, SLC1A2 overexpression, and in vitro glia–neuron assays.</p> Results <p>High-altitude hypoxia resulted in cognitive decline, dentate gyrus granule cell (DGC) injury, microglial activation, and astrocyte conversion to a complement-enriched reactive state. Cell–cell communication analysis revealed persistent suppression of the GLS–GRIK3–SLC1A2 axis, indicating impaired astrocytic glutamate clearance. Mechanistic experiments demonstrated that overexpression of SLC1A2 in astrocytes markedly enhances glutamate clearance, thereby associated with glutamate excitotoxic accumulation and improving neuronal cell viability. In in vivo models, IL1α knockdown or restoration of astrocytic SLC1A2 function alleviated glutamate homeostasis imbalance and was accompanied by improvements in cognitive behavioral performance.</p> Conclusion <p>This study identifies the IL1α–complement-enriched reactive astrocyte–SLC1A2 axis as a central driving mechanism underlying hypoxia-induced cognitive impairment, and suggests that targeting IL1α signaling and restoring SLC1A2 function may represent promising therapeutic strategies.</p> Graphical abstract <p></p>

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High-altitude hypoxia drives dentate gyrus neuronal vulnerability through an IL1α–astrocyte–SLC1A2 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月20日

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  • Yunan Zhang,
  • Zhexin Ni,
  • Tiantian Xia,
  • Nan Zhang,
  • Pan Shen,
  • Ningning Wang,
  • Zhijie Bai,
  • Yaolei Ma,
  • Rui Wang,
  • Dezhi Sun,
  • Shuman Li,
  • Chaoji Huangfu,
  • Yue Gao,
  • Wei Zhou

摘要

Background

High-altitude hypoxia is known to impair cognition, yet the underlying cellular and molecular mechanisms remain insufficiently understood. The hippocampus, especially the dentate gyrus (DG), is highly sensitive to hypoxic stress, but the pathways driving neuronal vulnerability and glial state transitions remain unclear.

Methods

We combined human cohort cognitive assessments, hypobaric chamber mouse models, and multi-omics profiling, including single-cell and spatial transcriptomics, spatial metabolomics, and cell–cell communication analyses, to construct an integrated map of hippocampal remodeling under hypoxia. Mechanistic validation was performed through IL1α knockdown, SLC1A2 overexpression, and in vitro glia–neuron assays.

Results

High-altitude hypoxia resulted in cognitive decline, dentate gyrus granule cell (DGC) injury, microglial activation, and astrocyte conversion to a complement-enriched reactive state. Cell–cell communication analysis revealed persistent suppression of the GLS–GRIK3–SLC1A2 axis, indicating impaired astrocytic glutamate clearance. Mechanistic experiments demonstrated that overexpression of SLC1A2 in astrocytes markedly enhances glutamate clearance, thereby associated with glutamate excitotoxic accumulation and improving neuronal cell viability. In in vivo models, IL1α knockdown or restoration of astrocytic SLC1A2 function alleviated glutamate homeostasis imbalance and was accompanied by improvements in cognitive behavioral performance.

Conclusion

This study identifies the IL1α–complement-enriched reactive astrocyte–SLC1A2 axis as a central driving mechanism underlying hypoxia-induced cognitive impairment, and suggests that targeting IL1α signaling and restoring SLC1A2 function may represent promising therapeutic strategies.

Graphical abstract