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Overactive EAAT1 Cl<sup>-</sup> channels impair GABAergic tonic inhibition in SLC1A3-associated episodic ataxia.

Overview

Authors: Yulia Kostritskaia1,2, Daniela Bulla-Miely3, Miriam Engels1, Jan Meyer4, Juliane L Berns5, Sabrina Behuet6, Sebastian Bludau6, Christine R Rose4, Albert Becker5, Thomas Gensch1, Ulrike B S Hedrich3, Christoph Fahlke1, Peter Kovermann1
ORCID iDs: Yulia Kostritskaia, Daniela Bulla-Miely, Miriam Engels, Jan Meyer, Juliane L Berns, Sabrina Behuet, Sebastian Bludau, Christine R Rose, Albert Becker, Thomas Gensch, Ulrike B S Hedrich, Christoph Fahlke, Peter Kovermann
  1. Institute of Biological Information Processing, Molekular- und Zellphysiologie (IBI-1), Forschungszentrum Jülich, 52428 Jülich, Germany
  2. Present Address: MSH Medical School Hamburg, 20457 Hamburg, Germany
  3. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
  4. Institute of Neurobiology, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
  5. Institute for Cellular Neurosciences II, Universitätsklinikum Bonn, 53127 Bonn, Germany
  6. Institute of Neuroscience and Medicine, Strukturelle und funktionelle Organisation des Gehirns (INM-1), Forschungszentrum Jülich GmbH, 52428 Jülich, Germany
Institutions: Forschungszentrum Jülich (Germany); MSH Medical School Hamburg – University of Applied Sciences and Medical University (Germany); Hertie Institute for Clinical Brain Research (Germany); University of Tübingen (Germany); Heinrich Heine University Düsseldorf (Germany); University of Bonn (Germany); University Hospital Bonn (Germany)
Journal: Acta neuropathologica communications, volume 14, issue 1, article 162
Dates: received 21 May 2026; accepted 31 July 2026; published online 4 August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s40478-026-02399-4 · PMID 42563189 · PMCID PMC13449690 · OpenAlex W7172450461
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), other condition (population), epilepsy (population), cellular / molecular (subfield)
Methods: Statistics, fMRI & imaging
Keywords: Glutamate transporters, Tonic inhibition, Epilepsy, Dentate gyrus, Radial glia-like cells, Chloride homeostasis
MeSH: Ataxia*, Excitatory Amino Acid Transporter 1*, gamma-Aminobutyric Acid*, Neural Inhibition*, Animals, Disease Models, Animal, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic (* major topic)
Topic: Neuroscience and Neuropharmacology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Citations: not cited yet (Europe PMC); 68 references in the paper
Research resources: with PATCHMASTER software RRID:SCR_000034, RRID:SCR_002716, GraphPad Prism 9.5.1 RRID:SCR_002798, Microcal-Origin RRID:SCR_002815, RRID:SCR_003210, DigiData 1420 with pClamp 10.6 software RRID:SCR_011323, using either an EPC10-USB amplifier RRID:SCR_018399, a Multiclamp 700B amplifier RRID:SCR_018455

Abstract

A missense variant in SLC1A3, which results in a proline to arginine substitution in the glial excitatory amino acid transporter 1 (EAAT1), causes a severe form of episodic ataxia type 6, characterized by recurrent attacks of ataxia and epilepsy. EAATs are dual function transport proteins, and the P290R variant reduces secondary active glutamate transport rates, while enhancing the anion channel activity. Here, we used complementary electrophysiological, imaging, biochemical and neuropathological techniques to characterize the cellular mechanisms underlying epileptic seizures in a mouse model of episodic ataxia type 6, the heterozygous Slc1a3P290R/+ mouse. Video-EEG recordings demonstrate frequent and severe spontaneous epileptic seizures in vivo. “Gliosis only” phenotype in the cerebrum of Slc1a3P290R/+ mice, which was restricted to the hippocampal formation, suggests that this brain structure may be involved in the development of epileptic seizure activity. Electrophysiological recordings from acute slices revealed a reduction in tonic GABAergic transmission in Slc1a3P290R/+ dentate gyrus granule cells, and to a lesser extent in cortical layer 2/3 pyramidal neurons before seizure onset. Phasic GABAergic and glutamatergic transmission remained unaltered in juvenile animals of the same developmental stage. There was no difference in expression levels of the GABAA receptor (GABAAR) δ subunits, suggesting that impaired tonic inhibition results from decreased extrasynaptic GABA concentrations. We identified enhanced GABA uptake by hippocampal radial glia-like cells (RGLs), caused by elevated GABA transporter 3 (GAT-3) expression and by an increased GABA transport driving force—due to lower intracellular chloride levels [Cl–]int – as cellular basis of impaired tonic inhibition. Our study demonstrates how increased EAAT1 chloride channel activity of the P290R variant can cause hyperexcitability by modifying synaptic GABA concentrations, while impaired EAAT1 glutamate transport leaves glutamatergic synaptic transmission in Slc1a3P290R/+ mice unaffected.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40478-026-02399-4.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Data availability

All data supporting this study are publicly available on GitHub at the following URL: https://github.com/peterkovermann/episodic_ataxia_6_II/

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 6 keywords, 10 MeSH terms, 68 references, 8 RRIDs.

Cite

This paper

Kostritskaia, Y., Bulla-Miely, D., Engels, M., Meyer, J., Berns, J. L., Behuet, S., Bludau, S., Rose, C. R., Becker, A., Gensch, T., Hedrich, U. B. S., Fahlke, C., & Kovermann, P. (2026). Overactive EAAT1 Cl<sup>-</sup> channels impair GABAergic tonic inhibition in SLC1A3-associated episodic ataxia. Acta neuropathologica communications, 14(1), 162. https://doi.org/10.1186/s40478-026-02399-4

BibTeX

@article{kostritskaia2026overactive,
author = {Kostritskaia, Yulia and Bulla-Miely, Daniela and Engels, Miriam and Meyer, Jan and Berns, Juliane L and Behuet, Sabrina and Bludau, Sebastian and Rose, Christine R and Becker, Albert and Gensch, Thomas and Hedrich, Ulrike B S and Fahlke, Christoph and Kovermann, Peter},
title = {{Overactive EAAT1 Cl\<sup\>-\</sup\> channels impair GABAergic tonic inhibition in SLC1A3-associated episodic ataxia}},
journal = {Acta neuropathologica communications},
year = {2026},
month = aug,
volume = {14},
number = {1},
pages = {162},
publisher = {BMC},
issn = {2051-5960},
doi = {10.1186/s40478-026-02399-4},
url = {https://doi.org/10.1186/s40478-026-02399-4},
pmid = {42563189},
pmcid = {PMC13449690}
}

RIS

TY - JOUR
AU - Kostritskaia, Yulia
AU - Bulla-Miely, Daniela
AU - Engels, Miriam
AU - Meyer, Jan
AU - Berns, Juliane L
AU - Behuet, Sabrina
AU - Bludau, Sebastian
AU - Rose, Christine R
AU - Becker, Albert
AU - Gensch, Thomas
AU - Hedrich, Ulrike B S
AU - Fahlke, Christoph
AU - Kovermann, Peter
TI - Overactive EAAT1 Cl<sup>-</sup> channels impair GABAergic tonic inhibition in SLC1A3-associated episodic ataxia
T2 - Acta neuropathologica communications
J2 - Acta Neuropathol Commun
PY - 2026
DA - 2026/08/04
VL - 14
IS - 1
SP - 162
SN - 2051-5960
PB - BMC
DO - 10.1186/s40478-026-02399-4
UR - https://doi.org/10.1186/s40478-026-02399-4
LA - en
ER -

CSL-JSON

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