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ResearchIn-Press PreviewNeuroscienceVascular biology Open Access | 10.1172/jci.insight.200411

Neuronal and astrocytic sodium-calcium exchanger differentially regulates calcium and sodium overload during ischemic stroke

Somayyeh Hamzei Taj,1 Pawan Kumar Thapaliya,2 Cordula Rakers,1 Niklas J. Gerkau,3 Christine R. Rose,3 Ghanim Ullah,2 and Gabor C. Petzold1

1Vascular Neurology Research Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

2Department of Physics, University of South Florida, Tampa, United States of America

3Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Hamzei Taj, S. in: PubMed | Google Scholar

1Vascular Neurology Research Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

2Department of Physics, University of South Florida, Tampa, United States of America

3Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Thapaliya, P. in: PubMed | Google Scholar

1Vascular Neurology Research Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

2Department of Physics, University of South Florida, Tampa, United States of America

3Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Rakers, C. in: PubMed | Google Scholar

1Vascular Neurology Research Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

2Department of Physics, University of South Florida, Tampa, United States of America

3Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Gerkau, N. in: PubMed | Google Scholar

1Vascular Neurology Research Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

2Department of Physics, University of South Florida, Tampa, United States of America

3Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Rose, C. in: PubMed | Google Scholar

1Vascular Neurology Research Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

2Department of Physics, University of South Florida, Tampa, United States of America

3Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Ullah, G. in: PubMed | Google Scholar

1Vascular Neurology Research Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

2Department of Physics, University of South Florida, Tampa, United States of America

3Institute of Neurobiology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Find articles by Petzold, G. in: PubMed | Google Scholar

Published June 2, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.200411.
Copyright © 2026, Hamzei Taj et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 2, 2026 - Version history
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Abstract

Spreading depolarizations (SDs) are propagating waves of near-complete breakdown of transmembrane ion gradients that occur during acute ischemic stroke and worsen outcome by driving calcium overload and glutamate release in neurons and astrocytes. The plasmalemmal sodium-calcium exchanger (NCX) plays a key role in such changes, in that the complex ionic disequilibrium during ischemia induces reverse-mode activity of NCX, leading to cellular calcium overload in exchange for sodium. However, the cell type-specific roles of NCX in neurons and astrocytes during SDs remain unclear. Here, we used ion and glutamate reporters in an in vivo stroke model in mice carrying inducible, cell-specific deletions of NCX isoform-1. Neuronal NCX1 deletion reduced neuronal and astrocytic calcium transients, increased neuronal sodium transients, decreased extracellular glutamate levels, and raised SD initiation threshold. In contrast, astrocytic NCX1 deletion increased sodium transients in both neurons and astrocytes, and increased neuronal calcium as well as extracellular glutamate levels. A computational model of ischemia confirmed that these effects are consistent with reverse-mode NCX1 activity. Together, these findings indicate opposing roles of reverse-mode NCX1 during ischemia. Neuronal NCX1 promotes SD susceptibility, calcium overload and glutamate release, whereas astrocytic NCX1 exerts protective effects by attenuating glutamate elevation and neuronal calcium accumulation.

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