Deep Behavioral Phenotyping of Novel Zebrafish Epilepsy Models

Project Summary/Abstract (from Parent R21NS138525) Patients diagnosed with genetic epilepsies suffer with severe seizures, neurobehavioral deficits and the uncertainty of a lifetime with diminished quality-of-life. Epilepsy in this population remains poorly controlled despite multiple antiseizure medications and is considered one of the greatest therapeutic challenges in the field. Despite tremendous effort, there remains a crucial need to study these epilepsy conditions at a preclinical level so we can identify new and safe drug treatments. Zebrafish mutants designed to represent these human genetic conditions would provide valuable tools for elucidating basic disease mechanisms and drug discovery. As such, we recently used CRISPR/Cas9 editing techniques to generate 37 different stable loss-of-function zebrafish mutants representing a broad spectrum of these epilepsies (Griffin et al. 2021). In this R21 proposal, would propose computational phenotyping of 12 different zebrafish mutants (arxa, cdkl5, chd2, depdc5, gabrb3, gabrg2, gnao1, pnpo, pcdh19, scn8a, stxbp1b, and syngap1b) and initiation of a program for large-scale drug screening. Using a recently developed high-resolution imaging system and machine learning based algorithms, this proposal offers an unbiased approach to behavioral phenotyping and drug discovery. This first-of-its-kind strategy could lead to a better understanding of a wide variety of currently intractable genetic epilepsies and new drug candidates for patients suffering with these conditions.