Abstract Ischemic stroke is a common cerebral disease. However, the treatment for the disease is limited. Daurian ground squirrel (GS;?Spermophilus dauricus), a hibernating mammalian species, is highly tolerant to ischemia. In the present study, GS neurons in a non‐hibernating state were found to be more resistant to oxygen–glucose deprivation (OGD), an ischemic model in vitro. We leveraged the differences in the endurance capacity of GS and rats to investigate the mechanisms of resistance to ischemia in GS?neurons. We first identified glutamate–aspartate transporter 1 (GLAST) as a cytoprotective factor that contributed to tolerance against OGD injury of GS neurons. The expression of GLAST in GS neurons was much higher than that in rat neurons. Overexpression of GLAST rescued viability in rat neurons, and GS neurons exhibited decreased viability following GLAST knockdown under OGD conditions. Mechanistically, more glutamate was transported into neurons after GLAST overexpression and served as substrates for ATP production. Furthermore, eukaryotic transcription initiation factor 4E binding protein 1 was downregulated by GLAST to rescue neuronal viability. Our findings not only revealed an important molecular mechanism underlying the survival of hibernating mammals but also suggested that neuronal GLAST may be a potential target for ischemic stroke therapy.
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