Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus

Henke, Christine; Töllner, Kathrin; Dijk, Roelof Maarten van; Miljanovic, Nina; Cordes, Thekla; Twele, Friederike; Bröer, Sonja; 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.; Köhling, Rüdiger; Birkenfeld, Andreas L.; Löscher, Wolfgang

doi:10.1016/j.nbd.2020.105018

Cited by 32 publications

(42 citation statements)

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“…Thus cumulative neuronal energy depletion as a consequence of increased interictal spiking may actually pave the way for a continuous lowering of the seizure threshold and generation of the next seizure event. Along this line, changes in TCA cycle activity can reduce ATP and adenosine concentrations with an impact on adenosine A 1 receptors subsequently affecting inwardly rectifying potassium channels and neuronal excitability 1, 30, 33, 34 . Our data, therefore, suggest that the complex alterations in energy metabolism may contribute to the high seizure frequency often characterizing the clinical phenotype of Dravet syndrome.…”

Section: Discussionmentioning

confidence: 70%

“…In the context of SLC13A5 deficiency, the interneuron energy hypothesis has been formulated, 31 which is based on the fact that inhibitory interneurons are characterized by a higher energy consumption than excitatory principal neurons 32 . As discussed previously, 30 energy deficits in inhibitory interneurons may result in disinhibition of excitatory neurons causing hyperexcitability. Thus cumulative neuronal energy depletion as a consequence of increased interictal spiking may actually pave the way for a continuous lowering of the seizure threshold and generation of the next seizure event.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, it needs to be taken into account that alterations in glucose metabolism and TCA cycle activity should not only be considered as a consequence of seizures and interictal activity, but can also contribute to an enhanced seizure susceptibility and ictogenesis. The pathophysiological relevance has been convincingly demonstrated by the characterization of genetic epilepsies with primary failure of energy supply related to a genetic deficiency of glucose transporter 1 or the sodium‐dependent citrate transporter NaCT encoded by the SLC13A5 gene 6, 30 . In the context of SLC13A5 deficiency, the interneuron energy hypothesis has been formulated, 31 which is based on the fact that inhibitory interneurons are characterized by a higher energy consumption than excitatory principal neurons 32 .…”

Section: Discussionmentioning

confidence: 99%

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Metabolomic signature of the Dravet syndrome: A genetic mouse model study

et al. 2021

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Objective Alterations in metabolic homeostasis can contribute to neuronal hyperexcitability and seizure susceptibility. Although the pivotal role of impaired bioenergetics is obvious in metabolic epilepsies, there is a gap of knowledge regarding secondary changes in metabolite patterns as a result of genetic Scn1a deficiency and ketogenic diet in the Dravet syndrome. Methods A comprehensive untargeted metabolomics analysis, along with assessment of epileptiform activity and behavioral tests, was completed in a Dravet mouse model. Data sets were compared between animals on a control and a ketogenic diet, and metabolic alterations associated with Dravet mice phenotype and ketogenic diet were identified. Results Hippocampal metabolomic data revealed complex alterations in energy metabolism with an effect of the genotype on concentrations of glucose and several glycolysis and tricarboxylic acid (TCA) cycle intermediates. Although low glucose, lactate, malate, and citrate concentrations became evident, the increase of several intermediates suggested a genotype‐associated activation of catabolic processes with enhanced glycogenolysis and glycolysis. Moreover, we observed an impact on the glutamate/γ‐aminobutyric acid (GABA)‐glutamine cycle with reduced levels of all components along with a shift toward an increased GABA‐to‐glutamate ratio. Further alterations comprised a reduction in hippocampal levels of noradrenaline, corticosterone, and of two bile acids. Significance Considering that energy depletion can predominantly compromise the function of GABAergic interneurons, the changes in energy metabolism may contribute to seizure susceptibility and ictogenesis. They may also explain the therapeutic potential of the ketogenic diet, which aims to shift energy metabolism toward a more fat‐based energy supply. Conversely, the increased GABA‐to‐glutamate ratio might serve as an endogenous compensatory mechanism, which can be further supported by GABAergic drugs, representing the mainstay of therapeutic management of Dravet syndrome. In view of a possible neuroprotective function of bile acids, it might be of interest to explore a possible therapeutic potential of bile acid–mediated therapies, already in discussion for neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Metabolomic signature of the Dravet syndrome: A genetic mouse model study

et al. 2021

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“…Notably, citrate levels were significantly increased in plasma and cerebrospinal fluid (CSF) in such epilepsy patients (Bainbridge et al, 2017). Mice deficient in this transporter accumulated citrate in CSF while plasma abundances were not affected; moreover, Slc13a5 -/mice exhibited an increased propensity for seizures as well as impaired neuronal function (Henke et al, 2020). While citrate's function in chelating metal cations has been hypothesized to drive this pathophysiology (Bhutia et al, 2017;Glusker, 1980), the mechanism(s) through which SLC13A5-deficiency drives pathogenesis in mammalian cells warrants further study.…”

Section: Introductionmentioning

confidence: 99%

NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

Kumar

Cordes

Thalacker‐Mercer

et al. 2021

Preprint

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Citrate lies at a critical node of metabolism linking tricarboxylic acid metabolism and fatty acid synthesis via acetyl-coenzyme A. Recent studies have linked the sodium citrate transporter (NaCT), encoded by SLC13A5, to dysregulated hepatic metabolism and pediatric epilepsy. To examine how NaCT-mediated citrate metabolism contributes to the pathophysiology of these diseases we applied 13C isotope tracing to SLC13A5-deficient hepatocellular carcinoma (HCC) cell lines and primary rat cortical neurons. Exogenous citrate contributed to intermediary metabolism at appreciable levels only under hypoxic conditions. In the absence of glutamine, citrate supplementation increased de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromised citrate uptake and catabolism. Citrate supplementation rescued Huh7 cell viability in response to glutamine deprivation and Zn2+ treatment, and these effects were mitigated by NaCT deficiency. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient limited conditions and may facilitate resistance to metal toxicity.

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“…This disease is characterized by neonatal epilepsy, delayed brain development and language skills, defective bone mineralization, and abnormal tooth development and enamalization. In contrast, Slc13a5 -null mice show minimal evidence of neurological dysfunction [ 13 ], but a robust beneficial metabolic phenotype relating to the loss of function of the transporter in the liver [ 8 ]; the beneficial features include resistance to diet-induced obesity, protection against diabetes and insulin resistance, and other clinical features of metabolic syndrome [ 8 ]. Considering the vastly differing consequences of NaCT deficiency in the brain versus the periphery, we recently hypothesized that it could be feasible to preferentially harness the beneficial effects of NaCT deficiency by developing inhibitors that only block the function of the transporter in the liver without having access to the brain [ 11 ].…”

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confidence: 99%

A home run for human NaCT/SLC13A5/INDY: cryo-EM structure and homology model to predict transport mechanisms, inhibitor interactions and mutational defects

Jaramillo-Martinez

Ganapathy

Urbatsch

2021

Biochemical Journal

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NaCT (SLC13A5) is a Na+-coupled transporter for citrate, which is expressed in the liver, brain, testes, and bone. It is the mammalian homolog of Drosophila INDY, a cation-independent transporter for citrate, whose partial loss extends lifespan in the organism. In humans, loss-of-function mutations in NaCT cause a disease with severe neurological dysfunction, characterized by neonatal epilepsy and delayed brain development. In contrast with humans, deletion of NaCT in mice results in a beneficial metabolic phenotype with protection against diet-induced obesity and metabolic syndrome; the brain dysfunction is not readily noticeable. The disease-causing mutations are located in different regions of human NaCT protein, suggesting that different mutations might have different mechanisms for the loss of function. The beneficial effects of NaCT loss in the liver versus the detrimental effects of NaCT loss in the brain provide an opportunity to design high-affinity inhibitors for the transporter that do not cross the blood-brain barrier so that only the beneficial effects could be harnessed. To realize these goals, we need a detailed knowledge of the 3D structure of human NaCT. The recent report by Sauer et al. in Nature describing the cryo-EM structure of human NaCT represents such a milestone, paving the way for a better understanding of the structure-function relationship for this interesting and clinically important transporter.

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Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus

Cited by 32 publications

References 95 publications

Metabolomic signature of the Dravet syndrome: A genetic mouse model study

Metabolomic signature of the Dravet syndrome: A genetic mouse model study

NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

A home run for human NaCT/SLC13A5/INDY: cryo-EM structure and homology model to predict transport mechanisms, inhibitor interactions and mutational defects

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