Human iPSC-derived neuronal models for in vitro neurotoxicity assessment

•hiPSC-derived models develop into networks with spontaneous activity and bursting.•hiPSC- derived models containing astrocytes exhibit synchronized activity.•Co-cultures can be modulated with seizurogenic compounds and neurotoxicants.•Inhibitory and excitatory neuron ratio may influence the chemica...

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Bibliographic Details
Published in:Neurotoxicology (Park Forest South) 2018-07, Vol.67, p.215-225
Main Authors: Tukker, Anke M., Wijnolts, Fiona M.J., de Groot, Aart, Westerink, Remco H.S.
Format: Article
Language:English
Subjects:
Alternatives to animal testing
Animal models
Astrocytes
Biocompatibility
Cortex
Dimethylmercury
Endosulfan
Firing pattern
Firing rate
Human induced pluripotent stem cell-derived neuronal models
In vitro neurotoxicity screening
In vivo methods and tests
Mercury (metal)
Methylmercury
Micro-Electrode array (MEA)
Microelectrodes
Mixed neuronal cultures
Neural networks
Neurons
Neurotoxicity
Organic chemistry
Picrotoxin
Pluripotency
Screening
Stem cells
Toxicity
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Summary:•hiPSC-derived models develop into networks with spontaneous activity and bursting.•hiPSC- derived models containing astrocytes exhibit synchronized activity.•Co-cultures can be modulated with seizurogenic compounds and neurotoxicants.•Inhibitory and excitatory neuron ratio may influence the chemical sensitivity.•hiPSC-derived models may already be used as prioritization tool in toxicity testing. Neurotoxicity testing still relies on ethically debated, expensive and time consuming in vivo experiments, which are unsuitable for high-throughput toxicity screening. There is thus a clear need for a rapid in vitro screening strategy that is preferably based on human-derived neurons to circumvent interspecies translation. Recent availability of commercially obtainable human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes holds great promise in assisting the transition from the current standard of rat primary cortical cultures to an animal-free alternative. We therefore composed several hiPSC-derived neuronal models with different ratios of excitatory and inhibitory neurons in the presence or absence of astrocytes. Using immunofluorescent stainings and multi-well micro-electrode array (mwMEA) recordings we demonstrate that these models form functional neuronal networks that become spontaneously active. The differences in development of spontaneous neuronal activity and bursting behavior as well as spiking patterns between our models confirm the importance of the presence of astrocytes. Preliminary neurotoxicity assessment demonstrates that these cultures can be modulated with known seizurogenic compounds, such as picrotoxin (PTX) and endosulfan, and the neurotoxicant methylmercury (MeHg). However, the chemical-induced effects on different parameters for neuronal activity, such as mean spike rate (MSR) and mean burst rate (MBR), may depend on the ratio of inhibitory and excitatory neurons. Our results thus indicate that hiPSC-derived neuronal models must be carefully designed and characterized prior to large-scale use in neurotoxicity screening.
ISSN:0161-813X
1872-9711
DOI:10.1016/j.neuro.2018.06.007