Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain
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 Ca<sup>2+</sup> 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.
Authors
- Neela K. Codadu (ORCID: https://orcid.org/0000-0002-5819-0340)
- Kirill E. Volynski (ORCID: https://orcid.org/0000-0001-8208-1905)
- Olga Kopach (ORCID: https://orcid.org/0000-0002-3921-3674)
- Leonid P. Savtchenko
- Robert E. Campbell (ORCID: https://orcid.org/0000-0003-0604-092X)
- Daman Rathore (ORCID: https://orcid.org/0000-0002-6301-9927)
- Robert C. Wykes (ORCID: https://orcid.org/0000-0002-6141-6822)
- Sheng-Yi Wu (ORCID: https://orcid.org/0000-0003-2336-0183)
- Olga Tyurikova (ORCID: https://orcid.org/0000-0003-0249-4844)
- Dmitri A. Rusakov (ORCID: https://orcid.org/0000-0001-9539-9947)
- Kaiyu Zheng (ORCID: https://orcid.org/0000-0002-9002-6292)
- Yi Shen (ORCID: https://orcid.org/0000-0003-4117-0279)
Institutions
- University of Alberta (CA)
- St George's, University of London (GB)
- London Centre for Nanotechnology (GB)
- Epilepsy Research UK (GB)
- MRC Prion Unit (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115299
- Citations
- 18
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 16.36
Funders
- Wellcome Trust
- National Centre for the Replacement, Refinement and Reduction of Animals in Research
- Medical Research Council
- Biotechnology and Biological Sciences Research Council