Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612030293X |
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| author | 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 |
| author_facet | 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 |
| author_sort | Christine Henke |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-15T00:26:12Z |
| format | Article |
| id | doaj.art-df9b3f253ba04e89ae8d4ee2953dca43 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-15T00:26:12Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-df9b3f253ba04e89ae8d4ee2953dca432022-12-21T22:42:10ZengElsevierNeurobiology of Disease1095-953X2020-09-01143105018Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampusChristine Henke0Kathrin Töllner1R. Maarten van Dijk2Nina Miljanovic3Thekla Cordes4Friederike Twele5Sonja Bröer6Vanessa Ziesak7Marco Rohde8Stefanie M. Hauck9Charlotte Vogel10Lisa Welzel11Tina Schumann12Diana M. Willmes13Anica Kurzbach14Nermeen N. El-Agroudy15Stefan R. Bornstein16Susanne A. Schneider17Jens Jordan18Heidrun Potschka19Christian M. Metallo20Rüdiger Köhling21Andreas L. Birkenfeld22Wolfgang Löscher23Section of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyInstitute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, GermanyInstitute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, GermanyDepartment of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USADepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyOscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, GermanyOscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, GermanyResearch Unit Protein Science, Helmholtz Center Munich, Neuherberg, GermanyDepartment of Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, GermanySection of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, GermanySection of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, GermanySection of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, GermanySection of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, GermanySection of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, GermanyDepartment of Neurology, Ludwig-Maximilians-University, Munich, GermanyInstitute for Aerospace Medicine, German Aerospace Center (DLR) and Chair for Aerospace Medicine, University of Cologne, Cologne, GermanyInstitute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, GermanyDepartment of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USAOscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, GermanySection of Metabolic and Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Technische Universität Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany; Corresponding author at: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, GermanyIn 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.http://www.sciencedirect.com/science/article/pii/S096999612030293XEpilepsy, NaCTProteomMetabolomParahippocampal cortex |
| spellingShingle | 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 Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus Neurobiology of Disease Epilepsy, NaCT Proteom Metabolom Parahippocampal cortex |
| title | Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus |
| title_full | Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus |
| title_fullStr | Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus |
| title_full_unstemmed | Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus |
| title_short | Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus |
| title_sort | disruption of the sodium dependent citrate transporter slc13a5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus |
| topic | Epilepsy, NaCT Proteom Metabolom Parahippocampal cortex |
| url | http://www.sciencedirect.com/science/article/pii/S096999612030293X |
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