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bioRxiv · 10.1101/2024.12.12.628225

Rapid long-range synaptic remodeling in hyperacute ischemic stroke

Chen, H.·Wei, Y.·Ruje, L.·Wan, Q.·Spivakov, M.·Glebov, O. O.
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Abstract

Physiological mechanisms of the key hyperacute (0-24 hours) stage of stroke remain incompletely understood, hampering development of new stroke therapies. Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders. Here, we describe rapid region-specific patterns of synaptic remodeling in stroke, arising within 4 hours of onset. While the ischemic core exhibits profound structural and functional synaptic decline, synapses in the mildly ischemic penumbra largely retain their structure, decreasing synaptic function. Conversely, synapses in the contralateral cortex across the brain show widespread structural and functional increase. Mechanistically, hyperacute stroke triggers synaptic recruitment of NMDA receptors in the ischemic core and penumbra, while NMDA receptor blockade exacerbates structural synaptic decline in the penumbra and abolishes contralateral synaptic enhancement. Proteomic analysis confirms cross-brain synaptic strengthening and reveals emergence of metabolic rearrangement in the penumbra, while RNAseq indicates broad downregulation of synaptic gene expression in the penumbra. These findings identify brain-wide homeostatic synaptic rebalancing as a potential mechanism for rapid-response functional compensation in early stroke, highlighting the extent of brain resilience to acute perturbation. HighlightsO_LIStroke induces rapid long-range synaptic enhancement in the contralateral hemisphere C_LIO_LINMDAR signaling orchestrates short and long-range synaptic remodeling in stroke C_LIO_LIProteomics and RNAseq reveal details of region-specific synaptic remodeling C_LI eTOC blurbWhat happens to synaptic communication across the brain during the first hours of stroke is unclear. We find that while synapses at the center of the stroke quickly fall apart, those in the surrounding area are protected and those in the opposite hemisphere are rapidly strengthened by the activity of NMDA-type glutamate receptors.

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Chen, H., Wei, Y., Ruje, L., Wan, Q., Spivakov, M., Glebov, O. O.. 2024-12-17. Rapid long-range synaptic remodeling in hyperacute ischemic stroke. https://doi.org/10.1101/2024.12.12.628225

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