摘要：SummaryIschemic stroke is the second leading cause of death worldwide. Following an ischemic event, neuronal death is triggered by uncontrolled glutamate release leading to overactivation of glutamate sensitiveN-methyl-d-aspartate receptor (NMDAR). For gating, NMDARs require not only the binding of glutamate, but also of glycine or a glycine-like compound as a co-agonist. Low glycine doses enhance NMDAR function, whereas high doses trigger glycine-induced NMDAR internalization (GINI)in vitro. Here, we report that following an ischemic event,in vivo, GINI also occurs and provides neuroprotection in the presence of a GlyT1 antagonist (GlyT1-A). Mice pretreated with a GlyT1-A, which increases synaptic glycine levels, exhibited smaller stroke volume, reduced cell death, and minimized behavioral deficits following stroke induction by either photothrombosis or endothelin-1. Moreover, we show evidence that in ischemic conditions, GlyT1-As preserve the vasculature in the peri-infarct area. Therefore, GlyT1 could be a new target for the treatment of ischemic stroke.Graphical abstractDisplay OmittedHighlights•GINI is a dynamic phenomenon which dampens NMDAR-mediated excitotoxicity during stroke•GlyT1-antagonists (GlyT1-As) trigger GINI during strokein vivo•GlyT1-As mitigate post-stroke behavioral deficits and preserve peri-infarct vasculature•GlyT1 could be a novel and viable therapeutic target for ischemic strokeNeuroscience; Molecular neuroscience; Cellular neuroscience
