Zebrafish models of Dravet syndrome: discovery of antiseizure drug leads and analysis of behavioural comorbidities

Doctoral thesis (2018)

Dravet syndrome (DS) is one of the most frequent genetic epilepsies, with an incidence of 1/30,000. Most DS patients are pharmacoresistant, in that they do not respond adequately to currently available ... [more ▼]

Dravet syndrome (DS) is one of the most frequent genetic epilepsies, with an incidence of 1/30,000. Most DS patients are pharmacoresistant, in that they do not respond adequately to currently available anticonvulsant drugs (ASDs). Beside the seizure occurrence in these patients, many DS patients also suffer from cognitive impairment that can be aggravated by some of the seizure medications prescribed. Preclinical models such as mouse models of Dravet syndrome have been developed and described to exhibit cognitive deficits similar to those of DS patients, but are only suitable for the evaluation of small number of compounds, thereby limiting their utility for drug discovery. An animal model with higher screening throughput would therefore be of value for drug discovery efforts focused on seizure reduction and decrease of the comorbidities associated with DS. Recent studies on zebrafish have demonstrated its ability to be a promising in vivo model for DS. Two different zebrafish DS models - one based on a loss-of-function mutation in the zebrafish ortholog of SCN1A, the other based on an antisense knockdown of this gene - exhibit seizure-like behaviour and epileptiform discharges that are exacerbated by hyperthermia. The mutant line was also described to display greater anxiety levels. In this Doctoral thesis project, we are investigating these zebrafish DS models with regard to (1) their seizure occurrence and potential reduction following exposure to several anticonvulsant drug candidates, and (2), their cognitive functions in order to determine possible similarities with cognitive impairment in human DS patients. Our results indicate these zebrafish DS models to exhibit memory impairment and higher anxiety levels. These findings provide an initial insight into the resemblance between human patients and zebrafish in terms of comorbidities. Finally, we also identified several novel anticonvulsant compounds and drug candidates with antiseizure activity in these zebrafish DS models. [less ▲]