BrainSphere Developmental Neurotoxicity
Exposure of the developing brain to environmental neurotoxicants can result in permanent alterations in structure and/or function. To investigate the effects of chemical exposures on neurodevelopment, human iPSC-derived neural BrainSpheres models have been utilized due to their ability to form mature neuronal populations and exhibit spontaneous electrical activity. To model neurodevelopment for toxicological screening, developing BrainSpheres were plated on high-density microelectrode arrays (hdMEA) three weeks after beginning differentiation. Starting two days post-plating, BrainSpheres were treated three times per week with compounds known to disrupt (assay positive controls; loperamide, dieldrin and deltamethrin), or without effect on (assay negative control; glyphosate) in vitro network formation. For 29 days, BrainSphere activity was recorded to measure neural network activity, general activity, and features of action potential propagation. Results demonstrate the ability of the assay to detect concentration-dependent and selective disruption of neural network formation. More specifically, results indicate that dieldrin, deltamethrin, and loperamide exposure decreased endpoints relating to neural network formation (e.g. burst frequency and burst peak). Further, evaluation of action potential propagation indicated concentration-dependent changes in several endpoints including neuron firing rate, axonal branch length, and conduction velocity. Interestingly, deltamethrin and loperamide decreased endpoints relating to action potential propagation, while dieldrin increased the neuron firing rate and amplitude at initiation site. These data indicate that BrainSpheres could be a valuable addition to the existing in vitro approaches for developmental neurotoxicity screening.
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