Enhancing glucose metabolism via gluconeogenesis is therapeutic in a zebrafish model of Dravet syndrome.

Energy-producing pathways are novel therapeutic targets for the treatment of neurodevelopmental disorders. Here, we focussed on correcting metabolic defects in a catastrophic paediatric epilepsy, Dravet syndrome which is caused by mutations in sodium channel NaV1.1 gene, . We utilized a translatable zebrafish model of Dravet syndrome () which exhibits key characteristics of patients with Dravet syndrome and shows metabolic deficits accompanied by down-regulation of gluconeogenesis genes, and . Using a metabolism-based small library screen, we identified compounds that increased gluconeogenesis via up-regulation of gene expression in larvae. Treatment with PK11195, a activator and a translocator protein ligand, normalized dys-regulated glucose levels, metabolic deficits, translocator protein expression and significantly decreased electrographic seizures in mutant larvae. Inhibition of in wild-type larvae mimicked metabolic and behaviour defects observed in mutants. Together, this suggests that correcting dys-regulated metabolic pathways can be therapeutic in neurodevelopmental disorders such as Dravet syndrome arising from ion channel dysfunction.