title: Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model.
abstract: Dravet syndrome (DS) is a severe epilepsy syndrome that starts within the first year of life. In a clinical study, add-on treatment with fenfluramine, a potent 5-hydroxytryptamine (5-HT) releaser activating multiple 5-HT receptor subtypes, made 70% of DS children seizure free. Others and we recently confirmed the efficacy of fenfluramine as an antiepileptiform compound in zebrafish models of DS. By using a large set of subtype selective agonists, in this study we examined which 5-HT receptor subtypes can be targeted to trigger antiseizure effects in homozygous scn1Lab(-/-) mutant zebrafish larvae that recapitulate DS well. We also provide evidence that zebrafish larvae express the orthologues of all human 5-HT receptor subtypes. Using an automated larval locomotor behavior assay, we were able to show that selective 5-HT1D-, 5-HT1E-, 5-HT2A-, 5-HT2C-, and 5-HT7-agonists significantly decreased epileptiform activity in the mutant zebrafish at 7 days post fertilization (dpf). By measuring local field potentials in the zebrafish larval forebrain, we confirmed the antiepileptiform activity of the 5-HT1D-, 5-HT2C-, and especially the 5-HT2A-agonist. Interestingly, we also found a significant decrease of serotonin in the heads of homozygous scn1Lab(-/-) mutants as compared to the wild type zebrafish, which suggest that neurochemical defects might play a crucial role in the pathophysiology of DS. Taken together, our results emphasize the high conservation of the serotonergic receptors in zebrafish larvae. Modulating certain serotonergic receptors was shown to effectively reduce seizures. Our findings therefore open new avenues for the development of future novel DS therapeutics.
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , 3000 Leuven, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Sourbron
authors.affiliation: Department of Biology, DePauw University , 1 East Hanna St., Greencastle, Indiana 46135, United States.
authors.forename: Henning
authors.initials: H
authors.lastname: Schneider
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , 3000 Leuven, Belgium.
authors.forename: Angéla
authors.initials: A
authors.lastname: Kecskés
authors.affiliation: Department of Biology, DePauw University , 1 East Hanna St., Greencastle, Indiana 46135, United States.
authors.forename: Yusu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biology, DePauw University , 1 East Hanna St., Greencastle, Indiana 46135, United States.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Buening
authors.affiliation: Department of Development and Regeneration, Section Pediatric Neurology, University Hospital KU Leuven , 3000 Leuven, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Lagae
authors.affiliation: Center for Neurosciences, C4N, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel , 1090 Brussels, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: de Witte
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D016896:Treatment Outcome; D015027:Zebrafish
chemical_list: D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin
keywords: Dravet syndrome; Serotonergic receptors; epilepsy; neurotransmitters; pharmacological modulation; zebrafish