Optimized Anti-Epileptic Screening Using Drosophila Models

Millions of people suffer from epilepsy in the US alone. In addition, many of these individuals do not respond well to current anti-seizure medications (pharmacoresistant epilepsy). Screening for new anti-seizure medications has proven difficult, especially using in vivo models of human epilepsy. We recently developed a model of pharmacoresistant epilepsy in the genetic model organism Drosophila melanogaster (fruit flies). Using this new in vivo model we screened a large chemical library of 1280 previously approved drugs and found 8 that could be repurposed, off label, for the treatment of pharmacoresistant epilepsy. Here we will improve the anti-seizure screening process in Drosophila using multi-fly video tracking tool (IowaFLI Tracker) and tethered fly electrophysiology to increase the screening efficiency of the system (R61 phase). Then we will use these new tools to screen a large collection of >3500 previously approved drugs from the Yale Center for Molecular Discovery for repurposing in humans (R33 phase). This project will not only revel new drugs that can be repurposed for the treatment of Duplication 15q pharmacoresistant epilepsy but will also provide powerful new tools for in vivo screening of anti-seizure drugs using other fly models of human epilepsy that already exist or could be easily constructed using syntenic mutation techniques.