Henke, Christine, Tollner, Kathrin, van Dijk, R. Maarten, Miljanovic, Nina, Cordes, Thekla ORCID: 0000-0002-8097-191X, Twele, Friederike, Broer, Sonja ORCID: 0000-0002-7969-6586, Ziesak, Vanessa, Rohde, Marco, Hauck, Stefanie M., Vogel, Charlotte, Welzel, Lisa, Schumann, Tina, Willmes, Diana M., Kurzbach, Anica, El-Agroudy, Nermeen N., Bornstein, Stefan R., Schneider, Susanne A., Jordan, Jens, Potschka, Heidrun, Metallo, Christian M., Kohling, Rudiger ORCID: 0000-0003-3330-4898, Birkenfeld, Andreas L. ORCID: 0000-0003-1407-9023 and Loscher, Wolfgang (2020). Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus. Neurobiol. Dis., 143. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1095-953X

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Henke, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tollner, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Dijk, R. MaartenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miljanovic, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cordes, TheklaUNSPECIFIEDorcid.org/0000-0002-8097-191XUNSPECIFIED
Twele, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broer, SonjaUNSPECIFIEDorcid.org/0000-0002-7969-6586UNSPECIFIED
Ziesak, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rohde, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauck, Stefanie M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, CharlotteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welzel, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumann, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willmes, Diana M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurzbach, AnicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El-Agroudy, Nermeen N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bornstein, Stefan R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, Susanne A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jordan, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Potschka, HeidrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Metallo, Christian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohling, RudigerUNSPECIFIEDorcid.org/0000-0003-3330-4898UNSPECIFIED
Birkenfeld, Andreas L.UNSPECIFIEDorcid.org/0000-0003-1407-9023UNSPECIFIED
Loscher, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-322260
DOI: 10.1016/j.nbd.2020.105018
Journal or Publication Title: Neurobiol. Dis.
Volume: 143
Date: 2020
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication: SAN DIEGO
ISSN: 1095-953X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AFFINITY ZINC INHIBITION; RAT MODEL FOCUS; PRIMARY CULTURES; PYRUVATE CARBOXYLATION; COUPLED DICARBOXYLATE; INSULIN-RESISTANCE; STATUS EPILEPTICUS; MOUSE MODEL; SEIZURES; EPILEPSYMultiple languages
NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32226

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