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

Epilepsies, Myoclonic/drug therapy*
Epilepsies, Myoclonic/genetics*
Epilepsies, Myoclonic/metabolism
Humans
Mutation/genetics*
Disease Models, Animal*
Serotonin Receptor Agonists/therapeutic use*
Base Sequence
Serotonin/metabolism
Treatment Outcome
Zebrafish
Animals
Receptors, Serotonin/genetics
Receptors, Serotonin/metabolism
Animals, Genetically Modified

(all 15)

PubMed

26822114 Full text @ ACS Chem. Neurosci.

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

Figures

Show all Figures

Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2
TL	standard conditions	Day 5	whole organism	RTPCR	Fig. 2

1 - 10 of 21

Show

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
scn1lab^s552/s552	standard conditions	Day 5	swim bladder absent, abnormal	Fig. 1
scn1lab^s552/s552	standard conditions	Day 5	trunk curved, abnormal	Fig. 1
scn1lab^s552/s552	standard conditions	Day 5	whole organism increased pigmentation, abnormal	Fig. 1
scn1lab^s552/s552	standard conditions	Days 7-13	locomotion increased occurrence, abnormal	Fig. 3
scn1lab^s552/s552	standard conditions	Days 7-13	locomotory behavior process quality, abnormal	Fig. 3
scn1lab^s552/s552	chemical treatment by environment: fenfluramine	Days 7-13	locomotion occurrence, ameliorated	Fig. 3
scn1lab^s552/s552	chemical treatment by environment: fenfluramine	Days 7-13	locomotory behavior process quality, ameliorated	Fig. 3
scn1lab^s552/s552	chemical treatment by environment: lorcaserin	Days 7-13	locomotion occurrence, ameliorated	Fig. 3
scn1lab^s552/s552	chemical treatment by environment: lorcaserin	Days 7-13	locomotory behavior process quality, ameliorated	Fig. 3

1 - 9 of 9

Show

Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
s552		Point Mutation	scn1lab

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Dravet syndrome	scn1lab^s552/s552	standard conditions	TAS
Dravet syndrome			TAS

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Sourbron et al., 2016 ZDB-PUB-160130-8 PMID:26822114

Serotonergic Modulation as Effective Treatment for Dravet syndrome in a Zebrafish Mutant Model

Sourbron et al., 2016

ZDB-PUB-160130-8
PMID:26822114