Society of Toxicology 2016

Pharmacological Responses in Cultured Human iPSC-Derived Cortical Neurons Using Multi-Electrode Array

Human induced pluripotent stem cell (hiPSC)-derived neurons may be used effectively for drug discovery and cell-based therapy. However, this is limited by the immaturity of cultured hiPSC-derived neurons and the lack of established functional evaluation methods. We used a multi-electrode array (MEA) system to investigate the effects of co-culturing astrocytes with hiPSC-derived cortical neurons on long-term culture, spontaneous firing activity, and drug responsiveness. The co-culture facilitated long-term culture of hiPSC-derived neurons over 400 days. Long-term spontaneous firing activity was also observed. After >3 months in culture, we observed synchronous burst firing activity due to synapse transmission within neuronal networks. Compared with rat neurons, hiPSC-derived neurons required a longer time to mature functionally. In drug response studies, addition of the synapse antagonist bicuculline, CNQX and AP5, and the agonist, L-glutamate, a kainic acid, induced significant changes in the firing rate and synchronised burst firing patterns. Furthermore, administration of pentylentetrazole (PTZ) induced epileptiform activity. Anti-epilepsy drugs, phenytoin and sodium valproate, reduced epileptiform activity. These results suggest that long-term electrophysiological measurements in hiPSC-derived neurons using an MEA system may be beneficial for clarifying the functions of human neuronal circuits and drug screening applications.

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The Use of iPSC-Derived Cells and Primary Cells as in vitro Models for Toxicity Screening

Toxicologists have access to a range of iPSC-derived cell types, including cardiomyocytes, hepatocytes and renal cells, used in toxicity screening. We discuss how these models are accurate and representative cell models, and how they can phase out inconsistencies and reduce the use of in vivo models.

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