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Editor's highlight: Evaluation of a Microelectrode Array-based Assay for Neural Network Ontogeny using Training Set Chemicals
Citation:
Brown, J., D. Hall, C. Frank, K. Wallace, W. Mundy, AND Tim Shafer. Editor's highlight: Evaluation of a Microelectrode Array-based Assay for Neural Network Ontogeny using Training Set Chemicals. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 154(1):126-139, (2016).
Impact/Purpose:
This manuscript presents proof-of-concept data for a high-throughput screen for chemical effects on development of functional activity in neural networks. Public concern that chemicals in the environment may contribute to neurodevelopmental effects is high due to increased prevalence of diseases such as ADHD and autism. However, tens of thousands of chemicals are lacking adequate testing for their potential to cause developmental neurotoxicity, and thus high-throughput assays are needed in order to test all of these chemicals. This assay is impactful because it is the only high-throughput assay to date that examines chemical effects on development of functional activity in networks of neurons. As some aspects of neural network activity are conserved both in vivo and in vitro, assessment of chemical effects on neural network development is important endpoint to consider when screening compounds for the potential to cause developmental neurotoxicity.
Description:
Thousands of compounds in the environment have not been characterized for developmental neurotoxicity (DNT) hazard. To address this issue, methods to screen compounds rapidly for DNT hazard evaluation are necessary and are being developed for key neurodevelopmental processes. In order to develop an assay for network formation, the current study evaluated effects of a training set of chemicals on network ontogeny by measuring spontaneous electrical activity in neural networks grown on microelectrode arrays (MEA). Rat (0-24 h old) primary cortical cells were plated in 48 well MEA plates and exposed to six compounds: acetaminophen, bisindolylmaleimide-1 (Bis-1), domoic acid, mevastatin, sodium orthovanadate, and loperamide for a period of 12 days. Spontaneous network activity was recorded on days 2, 5, 7, 9, and 12 and viability was assessed using the Cell Titer Blue® assay on day 12. Network activity (e.g. mean firing rate (MFR), burst rate (BR), etc), increased between days 5 and 12. Random Forest analysis indicated that across all compounds and times, temporal correlation of firing patterns (r), MFR, BR, #of active electrodes and % of spikes in a burst were the most influential parameters in separating control from treated wells. All compounds except acetaminophen (≤ 30 µM) caused concentration-related effects on one or more of these parameters. Domoic acid and sodium orthovanadate altered several of these parameters in the absence of cytotoxicity. Although cytotoxicity was observed with Bis1, mevastatin and loperamide, some parameters were affected by these compounds at concentrations below those resulting in cytotoxicity. These results demonstrate that this assay may be suitable for screening of compounds for DNT hazard identification.
