Traditional drug discovery programs for epilepsy target anticonvulsant effects and rely, almost exclusively, on induced seizure models in adult rodents. However, numerous genetic models that mimic many features of human epilepsies have now been described. These models provide important information but are not easily adapted to drug discovery programs. As a simple vertebrate species amenable to rapid genetic manipulation and high-throughput drug screening, we propose an alternative approach using mutant zebrafish (Danio rerio) with spontaneous recurrent seizure phenotypes (i.e., epilepsy) as a platform to identify new treatments for medically refractory epilepsy. We recently began to explore the possibility that spontaneous single-gene mutations in zebrafish - especially those mimicking catastrophic forms of epilepsy often seen in children - result in epileptic phenotypes. Zebrafish mutants featuring a loss-of-function sodium channel (Nav1.1/SCN1A) mutation (e.g., a gene family identified in children with Severe Myoclonic Epilepsy of Infancy and Dravet syndrome) were recently identified by our laboratory as epileptic zebrafish with phenotypes similar to the human condition. Using large-scale transcriptome analysis, automated behavioral tracking, in vivo electrophysiology and pharmacological approaches we describe a novel approach to further our understanding and potential treatment of debilitating epilepsy disorders associated with Nav1.1 mutation. In this EUREKA proposal we will use these mutant zebrafish in our efforts to (i) identify molecular targets for therapeutic treatment of DS/SMEI and (ii) identify drug candidates for therapeutic treatment of DS/SMEI. Our results promise to establish an alternative, zebrafish-based, approach for high-throughput small-molecule drug discovery targeted to monogenic epilepsy disorders seen primarily in children.
Epilepsy, a common neurological disorder, remains resistant to available drug treatments in nearly 300,000 patients. Despite the recent addition of new antiepileptic drugs there remains a substantial need for the identification of efficacious treatments for these medically refractory patients. Here we will use Nav1.1 mutant fish in a proof-of-concept small-molecule screens designed to identify novel pharmacological treatments.
|Griffin, Aliesha; Hamling, Kyla R; Hong, SoonGweon et al. (2018) Preclinical Animal Models for Dravet Syndrome: Seizure Phenotypes, Comorbidities and Drug Screening. Front Pharmacol 9:573|
|Griffin, Aliesha; Hamling, Kyla R; Knupp, Kelly et al. (2017) Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain 140:669-683|
|Grone, Brian P; Qu, Tiange; Baraban, Scott C (2017) Behavioral Comorbidities and Drug Treatments in a Zebrafish scn1lab Model of Dravet Syndrome. eNeuro 4:|
|Hong, SoonGweon; Lee, Philip; Baraban, Scott C et al. (2016) A Novel Long-term, Multi-Channel and Non-invasive Electrophysiology Platform for Zebrafish. Sci Rep 6:28248|
|Griffin, A; Krasniak, C; Baraban, S C (2016) Advancing epilepsy treatment through personalized genetic zebrafish models. Prog Brain Res 226:195-207|
|Kumar, Maneesh G; Rowley, Shane; Fulton, Ruth et al. (2016) Altered Glycolysis and Mitochondrial Respiration in a Zebrafish Model of Dravet Syndrome. eNeuro 3:|
|Grone, Brian P; Marchese, Maria; Hamling, Kyla R et al. (2016) Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish. PLoS One 11:e0151148|
|Grone, Brian P; Baraban, Scott C (2015) Animal models in epilepsy research: legacies and new directions. Nat Neurosci 18:339-43|
|Baraban, Scott C; Dinday, Matthew T; Hortopan, Gabriela A (2013) Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun 4:2410|
|Baraban, Scott C (2013) Forebrain electrophysiological recording in larval zebrafish. J Vis Exp :|
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