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Deletion of the Na+/citrate cotransporter SLC13A5 in mice reduces parahippocampal citrate levels and promotes an epileptic phenotype

Henke, C. and Toellner, K. and van Dijk, R.M. and Miljanovic, N. and Cordes, T. and Twele, F. and Bröer, S. and Ziesak, V. and Rohde, M. and Hauck, S. and Vogel, C. and Welzel, L. and Schumann, T. and Willmes, D. and Kurzbach, A. and El-Agroudy, N. and Bornstein, S.R. and Schneider, S. and Jordan, J. and Potschka, H. and Metallo, C.M. and Köhling, R. and Birkenfeld, A.L. and Löscher, W. (2020) Deletion of the Na+/citrate cotransporter SLC13A5 in mice reduces parahippocampal citrate levels and promotes an epileptic phenotype. Neurobiology of Disease, 143, p. 105018. Elsevier. doi: 10.1016/j.nbd.2020.105018. ISSN 0969-9961.

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Official URL: https://www.sciencedirect.com/science/article/pii/S096999612030293X?via%3Dihub

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.

Item URL in elib:https://elib.dlr.de/135829/
Document Type:Article
Title:Deletion of the Na+/citrate cotransporter SLC13A5 in mice reduces parahippocampal citrate levels and promotes an epileptic phenotype
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Henke, C.UNSPECIFIEDUNSPECIFIED
Toellner, K.Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyUNSPECIFIED
van Dijk, R.M.Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, GermanyUNSPECIFIED
Miljanovic, N.Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, GermanyUNSPECIFIED
Cordes, T.Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USAUNSPECIFIED
Twele, F.Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USAUNSPECIFIED
Bröer, S.Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyUNSPECIFIED
Ziesak, V.Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, GermanyUNSPECIFIED
Rohde, M.Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, GermanyUNSPECIFIED
Hauck, S.Research Unit Protein Science, Helmholtz Center Munich, Neuherberg, GermanyUNSPECIFIED
Vogel, C.Department of Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, GermanyUNSPECIFIED
Welzel, L.Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyUNSPECIFIED
Schumann, T.UNSPECIFIEDUNSPECIFIED
Willmes, D.University Hospital Dresden, Dresden, GermanyUNSPECIFIED
Kurzbach, A.University School of Medicine, Technische Universität DresdenUNSPECIFIED
El-Agroudy, N.Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, GermanyUNSPECIFIED
Bornstein, S.R.Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, GermanyUNSPECIFIED
Schneider, S.Department of Neurology, Ludwig-Maximilians-University, Munich, GermanyUNSPECIFIED
Jordan, J.Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany; Jens.Jordan (at) dlr.dehttps://orcid.org/0000-0003-4518-0706
Potschka, H.Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, GermanyUNSPECIFIED
Metallo, C.M.Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USAUNSPECIFIED
Köhling, R.Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, GermanyUNSPECIFIED
Birkenfeld, A.L.University Hospital Carl-Gustav Carus, Dresden, GermanyUNSPECIFIED
Löscher, W.Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyUNSPECIFIED
Date:September 2020
Journal or Publication Title:Neurobiology of Disease
Refereed publication:Yes
Open Access:Yes
Gold Open Access:Yes
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:143
DOI :10.1016/j.nbd.2020.105018
Page Range:p. 105018
Publisher:Elsevier
ISSN:0969-9961
Status:Published
Keywords:Epilepsy, NaCT; Proteom; Metabolom; Parahippocampal cortex
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Vorhaben Systemphysiologie (old)
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine
Institute of Aerospace Medicine > Cardiovascular Medicine in Aerospace
Institute of Aerospace Medicine > Leitungsbereich ME
Deposited By: Schrage, Larissa
Deposited On:01 Sep 2020 13:39
Last Modified:03 Feb 2021 04:12

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