Abstract
ABSTRACTDanio rerio (zebrafish) are a powerful experimental model for genetic and developmental studies. Adaptation of zebrafish to study seizures was initially established using the common convulsant agent pentylenetetrazole (PTZ). Larval PTZ-exposed zebrafish exhibit clear behavioral convulsions and abnormal electrographic activity, reminiscent of interictal and ictal epileptiform discharge. By using this model, our laboratory developed simple locomotion-based and electrophysiological assays to monitor and quantify seizures in larval zebrafish. Zebrafish also offer multiple advantages for rapid genetic manipulation and high-throughput phenotype-based drug screening. Combining these seizure assays with genetically modified zebrafish that represent Dravet syndrome, a rare genetic epilepsy, ultimately contributed to a phenotype-based screen of over 3500 drugs. Several drugs identified in these zebrafish screens are currently in clinical or compassionate-use trials. The emergence of this ‘aquarium-to-bedside’ approach suggests that broader efforts to adapt and improve upon this zebrafish-centric strategy can drive a variety of exciting new discoveries.
Highlights
Epilepsy is a common neurological disorder with a variety of underlying etiologies
The success of antiepileptic drugs (AEDs) in this population is likely to stem from the availability of 28 Federal Drug Administration (FDA)-approved drugs discovered in preclinical, primarily acute, rodent seizure models (Bourgeois, 1994; White, 1997; Loscher, 2002)
Our success with a larval zebrafish model for Dravet syndrome (DS) is but one small example of what may be possible. This system may not adapt to modeling forms of epilepsy that are acquired in adulthood or, all genetic forms of epilepsy, zebrafish models could offer similar routes to drug discovery for personalized medicine
Summary
Epilepsy is a common neurological disorder with a variety of underlying etiologies. In adults, acquired epilepsies – resulting from traumatic brain injury (Annegers and Coan, 2000), a history of febrile seizures (Offringa et al, 1992) or infection (van Baalen et al, 2017) – are most common. “Zebrafish disease models can be used to evaluate a rapidly growing number of candidate genes for neurological disorders, including rare genetic epilepsies apparent in children.”
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