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Using developing cortical cultures on microelectrode arrays to identify and prioritize compounds based on changes in network formation
Citation:
Shafer, Tim, C. Frank, J. Brown, K. Wallace, AND W. Mundy. Using developing cortical cultures on microelectrode arrays to identify and prioritize compounds based on changes in network formation. 2017 International Neurotoxicity Association Meeting, Florianopolis, N/A, BRAZIL, May 20 - 24, 2017.
Impact/Purpose:
This abstract describes the development and use of a neural network formation assay that can be used for developmental neurotoxicity screening.
Description:
Characterization of the potential adverse effects is lacking for tens of thousands of chemicals that are present in the environment, and characterization of developmental neurotoxicity (DNT) hazard lags behind that of other adverse outcomes (e.g. hepatotoxicity). This is due in part to the high cost and large number of animals needed to characterize DNT hazard. Thus, faster, less expensive approaches for DNT testing are needed. To address this need, we have developed a suite of assays to screen compounds for effects on critical neurodevelopmental processes, including network formation. Primary cortical neurons grown on microelectrode arrays (MEAs) spontaneously form connected networks and begin communicating. MEAs allow the spatial and temporal measurement of action potential spikes and bursts in these developing networks, and allow the assessment of chemical effects on network formation. To date, we have screened over 200 compounds using this assay, including a set of 60 compounds known to cause developmental neurotoxicity in vivo. Of these compounds, 49/60 altered at least one parameter of network development. By comparing the potency of compounds on network function to the potency of effects on cell viability, compounds can be prioritized for additional testing based on the specificity of effects on network formation. In addition, data from the MEA network formation assay can be combined with data from assays for neurite outgrowth, proliferation and other neurodevelopmental effects to develop a prioritization scheme based on multiple assays. This presentation will provide an overview of the assay, present examples of compound effects and show how the data can be used to provide information to regulatory decision-makers. (This work was supported by the US Environmental Protection Agency. This abstract does not reflect EPA policy).