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

Abstract

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. 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. 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. 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.