Abstract

Toxicological Responses in Human iPSC-derived Neurons Using MEA System

Ikuro Suzuki, Associate Professor, Tohoku Institute of Technology

The functional network of human induced pluripotent stem cell (hiPSC)-derived neurons is a potentially powerful in vitro model for evaluating drug toxicity. Epileptiform activity is one of phenomena in neuronal toxicology. To evaluate the dynamics of epileptiform activities and the effect of anti-convulsant drug in cultured hiPSC-derived neurons, we used the multielectrode array (MEA) system, where we simultaneously record extracellular potentials for 384 channels on 24-well plates. We firstly confirmed the modulation of activity by typical glutamatergic and GABAergic receptor antagonists/agonists in spontaneous firings. Spontaneous activities and typical responses against synaptic related drugs were detected with high S/N ratio using high-throughput MEA system. Next, we examined chemically evoked epileptiform activity. Electrophysiological seizes were induced by pentylentetrazole (PTZ), 4-Aminopyridine (4-AP), and kainic acid (KA), the most widely used chemical convulsant in animal models to screen for new anti-epilepsy drugs. We also examined the anti-convulsant effects of common clinical anti-epilepsy drugs (AEDs), phenytoin. PTZ, 4-AP and KA induced an increase in synchronized burst firings (SBFs) in a concentration-dependent manner. Phenytoin suppressed induced epileptiform activity. However, the patterns of epileptiform activities and phenytoin effects were different with respect to each epilepsy drugs. From these results, we suggest that the electrophysiological assay in cultured human iPSC-derived neuron using high-throughput MEA system is a useful to investigate the neuronal toxicity in drug screening and pharmacological effects of human neurological disease.