New work from the Esguerra group provides novel insight into disease mechanisms of Dravet syndrome

A new article from NCMM’s chemical neuroscience group published in Epilepsia sheds light on the early mechanisms underlying seizure onset in Dravet syndrome, a severe and devastating type of epilepsy that occurs in children and infants.

The zebrafish facility, NCMM. Photo: Øyvind Eide.

A severe type of epilepsy in children

Dravet syndrome is a severe and devastating type of epilepsy that occurs in children and  infants, and is very difficult to treat. A better understanding of the mechanisms within neuronal cells that promote disease progression could potentially improve our ability to treat this syndrome, which would have a substantial impact on patients and their families.

To address this need, the Esguerra group at NCMM have been working towards a better understanding of the earliest cellular defects driving the onset of seizures (the so-called ‘epileptogenic period’). In their latest article, published in the journal Epilepsia, the group analyzed brain development in a new zebrafish model of Dravet syndrome, enabling new insight into the mechanisms associated with disease development.

Establishing a zebrafish model: SCN1A mutations

One gene strongly associated with Dravet syndrome is SCN1A. This gene produces a protein that provides a channel for sodium ions to cross neuronal cell membranes, which, in turn, plays a role in neuronal cell signaling. Approximately 70-80% of Dravet syndrome patients are known to possess mutations in SCN1A, but how these mutations lead to disease progression is not fully understood.

The Esguerra group therefore analyzed a new zebrafish model of Dravet syndrome generated by using the gene-editing tool CRISPR-Cas9 to introduce a mutation in the zebrafish gene scn1lab – the zebrafish equivalent of SCN1Ain humans. They then performed behavioral analyses and measured different symptoms associated with seizures, followed by molecular profiling of neurons within the zebrafish in an attempt to gain a better understanding of the events that cause seizures to take place.

Neurotransmitter imbalance effectively treated with fenfluramine

These approaches revealed a potentially important imbalance between excitatory and inhibitory neurotransmitters that contributes to seizures and enhanced brain activity in zebrafish possessing the scn1lab1 mutation. Furthermore, treatment with the drug fenfluramine (pending approval for treatment of Dravet syndrome by the US Food and Drug Administration) reversed the neurotransmitter imbalance induced by scn1lab1 mutations and returned the zebrafish neurons to a healthy state.

These findings not only provide important new insights into the early stages of the development of Dravet syndrome, but provide first-time evidence for potential disease modification by fenfluramine. In addition, the zebrafish model established through this work offers a valuable new tool for studying the mechanisms underlying Dravet syndrome progression.

You can read the paper in full on the Wiley Online Library:

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome, Tiraboschi et al., Epilepsia 2020. doi: 10.1111/epi.16456

You can read more about the Esguerra group and their neuroscience research interests on their group page.