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

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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03744-z.