Detection of seizurogenic compounds in human and rat neurons in vitro: A multi-laboratory, multi-model assessment

Seizure liability remains a key risk for drug development and following chemical exposure. Advances in induced pluripotent stem cell (iPSC) biology and in vitro detection methodologies such as multielectrode array (MEA) offer an opportunity for a new paradigm in compound screening. Thus, a coordinated effort is needed to determine the methods, models, and parameters that are optimal for larger scale nonclinical assessment for seizure liability. Here we present the results of a multi-laboratory MEA assessment of seizurogenic detection in both human iPSC-derived neural cultures and primary rat cortical neurons. We evaluated the impact of 10 pro-convulsant compounds and 3 negative controls on spontaneous electrical activity in both types of neurons utilizing MEA. The work was conducted at 7 different laboratories across 3 continents. Both rat and human models showed similar changes to common metrics 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 laboratories 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 timepoints to assess seizure liability.