Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus.
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| Abstract |
In addition to tissues such as liver, the plasma membrane sodium-dependent citrate transporter, NaCT (SLC13A5), is highly expressed in brain neurons, but its function is not understood. Loss-of-function mutations in the human SLC13A5 gene have been associated with severe neonatal encephalopathy and pharmacoresistant seizures. The molecular mechanisms of these neurological alterations are not clear. We performed a detailed examination of a Slc13a5 deletion mouse model including video-EEG monitoring, behavioral tests, and electrophysiologic, proteomic, and metabolomic analyses of brain and cerebrospinal fluid. The experiments revealed an increased propensity for epileptic seizures, proepileptogenic neuronal excitability changes in the hippocampus, and significant citrate alterations in the CSF and brain tissue of Slc13a5 deficient mice, which may underlie the neurological abnormalities. These data demonstrate that SLC13A5 is involved in brain citrate regulation and suggest that abnormalities in this regulation can induce seizures. The present study is the first to (i) establish the Slc13a5-knockout mouse model as a helpful tool to study the neuronal functions of NaCT and characterize the molecular mechanisms by which functional deficiency of this citrate transporter causes epilepsy and impairs neuronal function; (ii) evaluate all hypotheses that have previously been suggested on theoretical grounds to explain the neurological phenotype of SLC13A5 mutations; and (iii) indicate that alterations in brain citrate levels result in neuronal network excitability and increased seizure propensity.
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| Authors | Christine Henke, Kathrin Töllner, R Maarten van Dijk, Nina Miljanovic, Thekla Cordes, Friederike Twele, Sonja Bröer, Vanessa Ziesak, Marco Rohde, Stefanie M Hauck, Charlotte Vogel, Lisa Welzel, Tina Schumann, Diana M Willmes, Anica Kurzbach, Nermeen N El-Agroudy, Stefan R Bornstein, Susanne A Schneider, Jens Jordan, Heidrun Potschka, Christian M Metallo, Rüdiger Köhling, Andreas L Birkenfeld, Wolfgang Löscher |
| Journal | Neurobiology of disease (Neurobiol Dis) Vol. 143 Pg. 105018 (09 2020) ISSN: 1095-953X [Electronic] United States |
| PMID | 32682952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. |
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