Journal Article

FZJ-2026-04029

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Overactive EAAT1 Cl− channels impair GABAergic tonic inhibition in SLC1A3-associated episodic ataxia

Kostritskaia, Y. ; Bulla-Miely, D. ; Engels, M.FZJ* ; Meyer, J. ; Berns, J. L. ; Behuet, S.FZJ* ; Bludau, S.FZJ* ; Rose, C. R. ; Becker, A. ; Gensch, T.FZJ* ; Hedrich, U. B. S. ; Fahlke, C.FZJ* ; Kovermann, P. (Corresponding author)FZJ*

2026
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s40478-026-02399-4  doi:10.34734/FZJ-2026-04029

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.

Note: Open Access funding enabled and organized by Projekt DEAL. The projectwas supported from the Federal Ministry of Education and Research (E-RAREnetwork Treat-ION: 01GM1907C to Ch.F. and 01GM1907G to U.H.; ProjectSynGluCross to C.R.R.) and the German Research Foundation (FOR 2795; FA301/13–1 to Ch.F.; Project #461542557, RO 2327/13–2,14–2 to C.R.R.).

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)
2. Strukturelle und funktionelle Organisation des Gehirns (INM-1)
3. International Helmholtz Research School of Biophysics and Soft Matter (IHRS-BioSoft)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
2. Treat-ION - Neue Therapien für neurologische Ionenkanal- und Transporterstörungen - Teilprojekt 6 Zelluläre Pathophysiologie (01GM1907C) (01GM1907C)

Appears in the scientific report 2026

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