Ischemic stroke triggers brain-wide synaptic remodeling within four hours

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Ischemic stroke triggers brain-wide synaptic remodeling within four hours

 Huanhuan Chen  

Ye Wei, 

Luminiţa Ruje, 

Fusheng Du, 

Zhendong Feng, 

Oleg O. Glebov  

Published: March 2, 2026 

https://doi.org/10.1371/journal.pbio.3003608 

Abstract

Physiological mechanisms of the key hyperacute (0–24 hours) stage of stroke are poorly understood, hampering the development of new therapies. 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.

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Citation: Chen H, Wei Y, Ruje L, Du F, Feng Z, Wan Q, et al. (2026) Ischemic stroke triggers brain-wide synaptic remodeling within four hours. PLoS Biol 24(3): e3003608. https://doi.org/10.1371/journal.pbio.3003608

Academic Editor: Richard Daneman, UCSD, UNITED STATES OF AMERICA

Received: August 26, 2025; Accepted: January 6, 2026; Published: March 2, 2026

Copyright: © 2026 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are contained within the paper and its Supporting information files, or freely available online. Proteomics data were analyzed by Oe Biotech using a proprietary pipeline. Mass spectrometry proteomics data is available at ProteomeXchange (https://proteomecentral.proteomexchange.org, dataset identifier PXD058834). Custom code for gene expression analysis has been uploaded to Zenodo (https://zenodo.org/records/17987265). RNAseq data is available at GEO (https://www.ncbi.nlm.nih.gov/geo/, accession number GSE283465). Numerical data is presented in S1 Table.