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Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders, yet its relevance in early stroke remains unclear. Here, we describe the emergence of distinct region-specific forms of synaptic remodeling following middle cerebral artery occlusion in rats, arising within the critical 4-hour period. Synapses within the severely ischemic core region were rapidly lost, while those in the mildly ischemic penumbra, albeit largely structurally intact, were functionally diminished. In contrast, the contralateral cortex exhibited increased synaptic staining and synaptic vesicle cycling. Systemic pharmacological blockade of NMDA-type glutamate receptors abolished contralateral synaptic increase and exacerbated synaptic decline in the penumbra. Proteomic and transcriptomic analyses showed that cross-brain synaptic plasticity is independent of local gene expression and revealed metabolic rearrangement and synaptic downregulation in the penumbra. These findings identify brain-wide synaptic rebalancing as a potential mechanism for rapid functional compensation in hyperacute stroke, highlighting the extent of brain response to acute perturbation.<\/jats:p>","DOI":"10.1371\/journal.pbio.3003608","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T18:37:36Z","timestamp":1772476656000},"page":"e3003608","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ischemic stroke triggers brain-wide synaptic remodeling within four hours"],"prefix":"10.1371","volume":"24","author":[{"given":"Huanhuan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lumini\u0163a","family":"Ruje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fusheng","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhendong","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Spivakov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3312-5470","authenticated-orcid":true,"given":"Oleg O.","family":"Glebov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"issue":"9","key":"pbio.3003608.ref001","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1177\/17474930221123175","article-title":"Global stroke statistics 2022","volume":"17","author":"T Thayabaranathan","year":"2022","journal-title":"Int J Stroke"},{"issue":"1","key":"pbio.3003608.ref002","doi-asserted-by":"crossref","DOI":"10.1016\/S2468-2667(21)00230-9","article-title":"Primary stroke prevention worldwide: translating evidence into action","volume":"7","author":"MO Owolabi","year":"2022","journal-title":"Lancet Public Health"},{"issue":"10","key":"pbio.3003608.ref003","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"20","author":"GBD 2019 Stroke Collaborators","year":"2021","journal-title":"Lancet Neurol"},{"issue":"5","key":"pbio.3003608.ref004","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1177\/1747493017711816","article-title":"Agreed definitions and a shared vision for new standards in stroke recovery research: The Stroke Recovery and Rehabilitation Roundtable taskforce","volume":"12","author":"J Bernhardt","year":"2017","journal-title":"Int J Stroke"},{"issue":"7","key":"pbio.3003608.ref005","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1161\/STROKEAHA.110.583815","article-title":"The \u201cgolden hour\u201d and acute brain ischemia: presenting features and lytic therapy in >30,000 patients arriving within 60 minutes of stroke onset","volume":"41","author":"JL Saver","year":"2010","journal-title":"Stroke"},{"issue":"1","key":"pbio.3003608.ref006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1052-3057(10)80125-9","article-title":"Editorial: time is brain!","volume":"3","author":"CR Gomez","year":"1993","journal-title":"J Stroke Cerebrovasc Dis"},{"issue":"14","key":"pbio.3003608.ref007","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1001\/jama.2015.3058","article-title":"Acute stroke intervention: a systematic review","volume":"313","author":"S Prabhakaran","year":"2015","journal-title":"JAMA"},{"issue":"8","key":"pbio.3003608.ref008","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1212\/WNL.56.8.1015","article-title":"Why are stroke patients excluded from TPA therapy? 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