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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\n                    <jats:italic>Slc1a3<\/jats:italic>\n                    <jats:sup>P290R\/+<\/jats:sup>\n                    mouse. Video-EEG recordings demonstrate frequent and severe spontaneous epileptic seizures in vivo. \u201cGliosis only\u201d phenotype in the cerebrum of\n                    <jats:italic>Slc1a3<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P290R\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    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\n                    <jats:italic>Slc1a3<\/jats:italic>\n                    <jats:sup>P290R\/+<\/jats:sup>\n                    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 GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor (GABA\n                    <jats:sub>A<\/jats:sub>\n                    R) \u03b4 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\u2014due to lower intracellular chloride levels [Cl\n                    <jats:sup>\u2013<\/jats:sup>\n                    ]\n                    <jats:sub>\n                      <jats:italic>int<\/jats:italic>\n                    <\/jats:sub>\n                    \u2013 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\n                    <jats:italic>Slc1a3<\/jats:italic>\n                    <jats:sup>P290R\/+<\/jats:sup>\n                    mice unaffected.\n                  <\/jats:p>","DOI":"10.1186\/s40478-026-02399-4","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:20:11Z","timestamp":1785842411000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Overactive EAAT1 Cl\u2212 channels impair GABAergic tonic inhibition in SLC1A3-associated episodic ataxia"],"prefix":"10.1186","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-2918","authenticated-orcid":false,"given":"Yulia","family":"Kostritskaia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1241-1853","authenticated-orcid":false,"given":"Daniela","family":"Bulla-Miely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7801-4929","authenticated-orcid":false,"given":"Miriam","family":"Engels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3351-8653","authenticated-orcid":false,"given":"Jan","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5003-4922","authenticated-orcid":false,"given":"Juliane L.","family":"Berns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4975-786X","authenticated-orcid":false,"given":"Sabrina","family":"Behuet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6173-9050","authenticated-orcid":false,"given":"Sebastian","family":"Bludau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9684-3592","authenticated-orcid":false,"given":"Christine R.","family":"Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2661-3705","authenticated-orcid":false,"given":"Albert","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-4705","authenticated-orcid":false,"given":"Thomas","family":"Gensch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3801-1306","authenticated-orcid":false,"given":"Ulrike B. 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