PUBLICATION
Serotonergic Modulation as Effective Treatment for Dravet syndrome in a Zebrafish Mutant Model
- Authors
- Sourbron, J., Schneider, H., Kecskés, A., Liu, Y., Buening, E.M., Lagae, L., Smolders, I., de Witte, P.A.
- ID
- ZDB-PUB-160130-8
- Date
- 2016
- Source
- ACS Chemical Neuroscience 7(5): 588-98 (Journal)
- Registered Authors
- Schneider, Henning
- Keywords
- Serotonergic receptors, pharmacological modulation, neurotransmitters, epilepsy, Dravet syndrome, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Base Sequence
- Disease Models, Animal*
- Epilepsies, Myoclonic/drug therapy*
- Epilepsies, Myoclonic/genetics*
- Epilepsies, Myoclonic/metabolism
- Humans
- Mutation/genetics*
- Receptors, Serotonin/genetics
- Receptors, Serotonin/metabolism
- Serotonin/metabolism
- Serotonin Receptor Agonists/therapeutic use*
- Treatment Outcome
- Zebrafish
- PubMed
- 26822114 Full text @ ACS Chem. Neurosci.
Citation
Sourbron, J., Schneider, H., Kecskés, A., Liu, Y., Buening, E.M., Lagae, L., Smolders, I., de Witte, P.A. (2016) Serotonergic Modulation as Effective Treatment for Dravet syndrome in a Zebrafish Mutant Model. ACS Chemical Neuroscience. 7(5):588-98.
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, led to seizure-freedom in 70% of DS children. Others and we recently confirmed the efficacy of fenfluramine as an anti-epileptiform 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 anti-seizure 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 anti-epileptiform 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 wildtype 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping