Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain
Summary: Intense brain activity elevates extracellular potassium, potentially leading to overexcitation and seizures. Astrocytes are crucial for restoring healthy potassium levels, and an emerging focus on their Kir4.1 channels has reopened the quest into the underlying mechanisms. We find that the...
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000701 |
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| author | Olga Tyurikova Olga Kopach Kaiyu Zheng Daman Rathore Neela Codadu Sheng-Yi Wu Yi Shen Robert E. Campbell Rob C. Wykes Kirill Volynski Leonid P. Savtchenko Dmitri A. Rusakov |
| author_facet | Olga Tyurikova Olga Kopach Kaiyu Zheng Daman Rathore Neela Codadu Sheng-Yi Wu Yi Shen Robert E. Campbell Rob C. Wykes Kirill Volynski Leonid P. Savtchenko Dmitri A. Rusakov |
| author_sort | Olga Tyurikova |
| collection | DOAJ |
| description | Summary: Intense brain activity elevates extracellular potassium, potentially leading to overexcitation and seizures. Astrocytes are crucial for restoring healthy potassium levels, and an emerging focus on their Kir4.1 channels has reopened the quest into the underlying mechanisms. We find that the Kir4.1 level in individual astrocytes sets the kinetics of their potassium and glutamate uptake current. Combining electrophysiology with multiplexed optical sensor imaging and FLIM reveals that rises in extracellular potassium would normally boost presynaptic Ca2+ entry and release probability at excitatory synapses unless such synapses are surrounded by the Kir4.1-overexpressing astrocytes. Inside the territories of Kir4.1-overexpressing astrocytes, high-frequency afferent stimulation fails to induce long-term synaptic potentiation, and the high-potassium waves of cortical spreading depolarization are markedly attenuated. Biophysical exploration explains how astrocytes can regulate local potassium homeostasis by engaging Kir4.1 channels. Our findings thus point to a fundamental astrocytic mechanism that can restrain the activity-driven rise of excitability in brain circuits. |
| format | Article |
| id | doaj-art-59055e0d60f04ef4afa0ca0f5ac6bb7b |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-59055e0d60f04ef4afa0ca0f5ac6bb7b2025-08-20T02:13:48ZengElsevierCell Reports2211-12472025-02-0144211529910.1016/j.celrep.2025.115299Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brainOlga Tyurikova0Olga Kopach1Kaiyu Zheng2Daman Rathore3Neela Codadu4Sheng-Yi Wu5Yi Shen6Robert E. Campbell7Rob C. Wykes8Kirill Volynski9Leonid P. Savtchenko10Dmitri A. Rusakov11Department of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; Corresponding authorDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; Neuroscience and Cell Biology Research Institute, City St George's, University of London, Cranmer Terrace, London SW17 0RE, UKDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKDepartment of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, CanadaDepartment of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, CanadaDepartment of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada; Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, JapanDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; Division of Neuroscience & Centre for Nanotechnology in Medicine, The University of Manchester, Manchester M13 9PL, UKDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UKDepartment of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; Corresponding authorSummary: Intense brain activity elevates extracellular potassium, potentially leading to overexcitation and seizures. Astrocytes are crucial for restoring healthy potassium levels, and an emerging focus on their Kir4.1 channels has reopened the quest into the underlying mechanisms. We find that the Kir4.1 level in individual astrocytes sets the kinetics of their potassium and glutamate uptake current. Combining electrophysiology with multiplexed optical sensor imaging and FLIM reveals that rises in extracellular potassium would normally boost presynaptic Ca2+ entry and release probability at excitatory synapses unless such synapses are surrounded by the Kir4.1-overexpressing astrocytes. Inside the territories of Kir4.1-overexpressing astrocytes, high-frequency afferent stimulation fails to induce long-term synaptic potentiation, and the high-potassium waves of cortical spreading depolarization are markedly attenuated. Biophysical exploration explains how astrocytes can regulate local potassium homeostasis by engaging Kir4.1 channels. Our findings thus point to a fundamental astrocytic mechanism that can restrain the activity-driven rise of excitability in brain circuits.http://www.sciencedirect.com/science/article/pii/S2211124725000701CP: Neuroscience |
| spellingShingle | Olga Tyurikova Olga Kopach Kaiyu Zheng Daman Rathore Neela Codadu Sheng-Yi Wu Yi Shen Robert E. Campbell Rob C. Wykes Kirill Volynski Leonid P. Savtchenko Dmitri A. Rusakov Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain Cell Reports CP: Neuroscience |
| title | Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain |
| title_full | Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain |
| title_fullStr | Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain |
| title_full_unstemmed | Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain |
| title_short | Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain |
| title_sort | astrocyte kir4 1 expression level territorially controls excitatory transmission in the brain |
| topic | CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000701 |
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