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. Overall design: RNAseq profiling of whole-brain tissues (brain) and biochemically purified synaptosomes (syn) from frontal cortex of 3 rats (rep 1, 2, 3) subjected to middle cerebral artery occlusion for 4 hours. For each brain, 3 regions were analysed, namely ischemic core (4c), surrounding penumbra (4p), and contralateral hemisphere (4z). For control (CA), 3 rats (rep 1, 2, 3) were subjected to sham surgery without occlusion, and whole-brain tissues and synaptosome samples were prepared as described above, with 1 region from each brain.