Camila Esguerra

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome 

Dravet syndrome (DS), a severe, developmental and epileptic encephalopathy, is characterized by recurrent, intractable seizures. In 80% of cases, the disease is caused by de novo mutations in the SCN1A gene, encoding the alpha subunit of voltage-gated sodium channel Na v 1.1. Currently approved anti-seizure drugs cannabidiol and stiripentol, do not modify the disease, but rather, act to ameliorate seizures. Thus, the identification of new therapeutic treatment options as well as pathological mechanisms leading to DS is crucial. In our latest publication, we described a new zebrafish model of DS. scn1lab -/- larvae exhibit spontaneous seizures and display hallmarks of DS. Using a transgenic reporter line, we observed a 40% decrease in dendritic arborization of GABA-ergic neuron of the optic tectum in 6-day-old scn1lab -/- larvae. It was accompanied by an increase in neuronal proliferation in the same structure. Next, we assessed the activity of fenfluramine, a potent serotonin receptor agonist, to counteract the above-mentioned changes in DS mutants. Here, we observed that chronic fenfluramine treatment not only decreased the number of seizures, but also reversed the changes in GABA-ergic neurons arborization, as well as hyperproliferation. In conclusion, our study provides new evidence for (1) early DS-linked epileptogenesis mechanisms and (2) disease-modifying effects of fenfluramine in DS.