New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

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This study used zebrafish to try to gain insights into the very earliest neurodevelopmental effects occurring in Dravet syndrome. In previous posts we have explained that appropriately mutated zebrafish are now an established and useful model for Dravet syndrome. The authors performed behavioral analysis, measured convulsions, and did extensive examination of the functional and morphological profiles of neurons, even to the level of individual cells, in zebrafish larvae.

They observed changes in the populations of various cell types in the brain composition of the Dravet larvae with respect to wild type. Also, the most striking observation was a significant reduction in the dendritic branching of GABAergic neurons (neurons form branches, that look very much like a tree’s branches, and their density and grouping patterns are highly correlated to the function of the neuron). The authors postulate that this reduction of branching in inhibitory neurons causes an inhibitory-to-excitatory neurotransmitter imbalance that contributes to seizures and altered electrical brain activity in the Dravet larvae.

The research team decided to use their system to try to investigate the effects of drugs used to treat Dravet syndrome. They found that chronic administration of fenfluramine completely restored dendritic branching numbers back to normal in the mutant larvae. They followed up with data suggesting that the fenfluramine response was specific and not simply due to seizure inhibition, since chronic treatment using diazepam, which attenuated seizures, did not restore dendritic branching numbers to normal.

Tiraboschi, E. et al. New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome. Epilepsia 2020 Feb 24 [Epub ahead of print]. DOI: 10.1111/epi.16456.

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