Exciting Models. Exploring the Applicability of Human Neuronal Cell Models for In Vitro Neurotoxicity Screening and Seizure Liability Assessment

Abstract

Worldwide more and more people depend on medication for mental or neurodegenerative diseases, thereby increasing the demand for drugs affecting the central nervous system (CNS). Because these drugs have to cross the blood-brain-barrier, they have an increased risk on adverse side effects in the CNS. One of the most severe adverse effects is a seizure. During a seizure, neurons fire in a hyper-active and -synchronous manner. Currently, the potential of a drug to cause a seizure is investigated either in vivo or ex vivo. This animal research is expensive, time consuming and ethically debated. On top of that, rodents differ from humans and therefore the outcome is not always predictive for human risk. There is thus a clear need for alternative test strategies, preferably using human cells. The recent introduction of human induced pluripotent stem cell (hiPSC)-derived neurons offers opportunities. This research investigates the use of hiPSC-derived neurons as an alternative for animal studies. We showed that mono-cultures of purely neurons form active neuronal networks. Adding astrocytes and additional changes in the ratio of excitatory glutamatergic and inhibitory GABAergic neurons increases neuronal (network) bursting and synchronicity, making the networks more resemble the human in vivo situation. Exposure of these co-cultures to known seizurogenic compounds results in in vitro increased network activity indicating the seizurogenic potential of the compound. This research thus shows that these hiPSC-derived neurons in combination with astrocytes can already be used for in vitro seizure liability assessment thereby paving the way to animal free neurotoxicological research.