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Henke, C. ; Töllner, K.* ; van Dijk, R.M.* ; Miljanovic, N.* ; Cordes, T.* ; Twele, F.* ; Bröer, S.* ; Ziesak, V.* ; Rohde, M.* ; Hauck, S.M. ; Vogel, C.* ; Welzel, L.* ; Schumann, T. ; Willmes, D.M. ; Kurzbach, A. ; El-Agroudy, N.N. ; Bornstein, S.R.* ; Schneider, S.A.* ; Jordan, J.* ; Potschka, H.* ; Metallo, C.M.* ; Köhling, R.* ; Birkenfeld, A.L. ; Löscher, W.*

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. 143:105018 (2020)
Verlagsversion Forschungsdaten DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Epilepsy, Nact ; Proteom ; Metabolom ; Parahippocampal Cortex; Affinity Zinc Inhibition; Rat Model Focus; Primary Cultures; Pyruvate Carboxylation; Coupled Dicarboxylate; Insulin-resistance; Status Epilepticus; Mouse Model; Seizures; Epilepsy
ISSN (print) / ISBN 0969-9961
e-ISSN 1095-953X
Quellenangaben Band: 143, Heft: , Seiten: , Artikelnummer: 105018 Supplement: ,
Verlag Elsevier
Verlagsort 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)
Core Facility Metabolomics & Proteomics (CF-MPC)