Rapid short- and long-range synaptic remodeling in hyperacute ischemic stroke

Physiological mechanisms of the pivotal hyperacute (0-24 hours) stage of stroke remain incompletely understood. Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders. Here, we describe distinct region-specific patterns of synaptic remodeling across the brain, arising within 1-4 hours of stroke onset. As synapses in the ischemic core decline profoundly, mildly ischemic penumbra retains synaptic structure albeit with decreased function, whereas the contralateral hemisphere shows an increase in synaptic size and function. Mechanistically, stroke leads to synaptic recruitment of NMDA-type glutamate receptors (NMDARs) in ischemic core and penumbra, and NMDAR signaling blockade triggers synaptic loss in the penumbra and abolishes contralateral synaptic strengthening. Proteomic analysis confirms synaptic enhancement in the contralateral hemisphere and reveals rapid onset of metabolic rearrangement in the penumbra, while RNAseq shows decline of synaptic gene expression in the penumbra. These findings identify brain-wide synaptic rebalancing as a potential mechanism for rapid-response homeostatic compensation in stroke, highlighting an extent of brain resilience to acute functional perturbation.卒中关键的超急性期（0~24小时）的病理生理机制尚未完全阐明。突触可塑性（synaptic plasticity）已被证实与神经退行性疾病及神经发育障碍的早期进程密切相关。本研究报道了卒中发作后1~4小时内全脑范围内出现的、具有显著脑区特异性的突触重塑（synaptic remodeling）模式。缺血核心区（ischemic core）的突触发生显著退变，轻度缺血半暗带（ischemic penumbra）虽功能有所下降，但仍保留了突触结构；而对侧半球（contralateral hemisphere）的突触体积与功能均出现提升。从机制层面来看，卒中可促使缺血核心区与半暗带内的突触募集NMDA型谷氨酸受体（NMDARs）；阻断NMDAR信号通路则会引发半暗带内的突触丢失，并抵消对侧半球的突触强化效应。蛋白质组学分析证实了对侧半球的突触增强效应，并揭示了半暗带内代谢重排的快速启动；RNA测序（RNAseq）结果显示半暗带内突触相关基因的表达水平出现下调。本研究发现全脑范围内的突触再平衡是卒中后快速应答性稳态代偿的潜在机制，该结果凸显了大脑对急性功能紊乱的耐受能力。