Shafer HESI MEA Data for Seizurogenic Potential
Seizure liability remains a key risk for the development of drugs and following chemical exposure. Advances in stem cell biology and in vitro detection methodologies such as microelectrode array (MEA) offer an opportunity for a new paradigm in screening. Thus, a coordinated effort is needed to determine the methods, models, and parameters that are optimal for larger scale pre-clinical compound screening for seizure liability. This data was used in a multi-laboratory MEA assessment of seizure detection in human induced pluripotent stem cell (hiPSC) neurons and in rat cortical neurons. We assessed the impact of 10 pro-seizurogenic compounds (3 GABA receptor antagonists, 3 CNS active therapies, 4 other reported seizurogenic compounds) and 3 negative controls on spontaneous electrical activity in both human and rat neurons on MEA. This was one of 7 different laboratories across 3 continents that provided data. Both rat and human models showed common changes to key MEA parameters such as mean of interspike distance (mean ISI) and median burst rate across facilities and across all compounds, with more consistency in the human model. Regarding differences between compounds, seizurogenic compounds caused the largest changes in MEA profile and the parameter with the most commonality was mean ISI, which was decreased in all tested compounds except picrotoxin. Overall, all centers generated MEA data indicative of a seizurogenic phenotype but the human model was more consistent across sites, despite some variation in protocols. Lessons learned from this work include having a clear aim before choosing a model, understanding and characterizing the model in the actual test site, and carefully considering the most appropriate times to assess seizure liability, since these parameters can clearly impact the outcome.