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.

Zebrafish Models of Neurodevelopmental Disorders: Past, Present, and Future

“…A subsequent study found that clemizole has activity at 5-HT 2A and 5-HT 2B receptors in a radioligand binding assay, suggesting that a serotonergic mechanism may be responsible for its anti-epileptic activity (Griffin et al, 2017). Interestingly, fenfluramine, an inducer of serotonin (5-hydroxytrypamine, 5-HT) release, which was found to have some efficacy in improving seizures in individuals with Dravet syndrome (Ceulemans et al, 2012), also reduced seizure activity in zebrafish scn1lab mutants and morphants, suggesting conservation of pharmacological pathways (Dinday and Baraban, 2015; Zhang et al, 2015; Sourbron et al, 2016). …”

“…Based on the serotonergic mechanism of fenfluramine, (Sourbron et al, 2016) tested selective 5-HT receptor agonists in scn1lab mutants and found that 5-HT 1D , 5-HT 2C , and 5-HT 2A agonists reverse electrographic seizure activity. Also, Griffin et al (2017) screened a library of 5-HT-modulating compounds and found that lorcaserin and trazodone rescued seizure activity.…”

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Sourbron et al (2016) were able to demonstrate that selective 5-HT 1D -, 5-HT 1E -, 5-HT 2A -, 5-HT 2C -, and 5-HT 7 -R agonists significantly decreased epileptiform activity in a homozygous sodium voltage gated channel alpha subunit 1 (SCN1A) mutant zebrafish model for Dravet syndrome (Sourbron et al, 2016). …”

MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate

“…Indeed, it has been shown that a genetic manipulation of zebrafish can result in reduced 5-HT content and increased seizure activity (Sourbron et al, 2016). However, Giorgi et al (2005) have reported that dosage regimens of MDMA that do not result in 5-HT depletion still result in increased seizure susceptibility.…”