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Functional Evaluation of Biological Neurotoxins in Networked Cultures of Stem Cell-derived Central Nervous System Neurons
Published on: February 5, 2015
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Multi-well microelectrode array recordings detect neuroactivity of ToxCast compounds.
Pablo Valdivia1, Matt Martin2, William R LeFew3
1Axion Biosystems, Atlanta, GA, United States.
Neurotoxicology
|July 6, 2014
Summary
Multi-well microelectrode arrays (MEAs) efficiently screen chemical neurotoxicity. This method aligns with ion channel assay predictions but shows limitations with nicotinic compounds.
Area of Science:
- Neuroscience
- Toxicology
- Assay Development
Background:
- Spontaneous neuronal activity in cultures is sensitive to chemical and drug effects.
- Multi-well microelectrode array (mwMEA) systems enhance throughput for chemical screening.
- The US Environmental Protection Agency's (EPA) ToxCast program utilizes high-throughput screening assays.
Purpose of the Study:
- To evaluate the utility of mwMEAs for screening EPA ToxCast compounds for neurotoxic effects.
- To assess the concordance between mwMEA results and ToxCast Novascreen ion channel (NVS_IC) assay predictions.
- To identify potential neurotoxicants and understand discrepancies between screening platforms.
Main Methods:
- Primary cortical neurons in 48-well MEA plates were exposed to ToxCast compounds.
- Baseline neuronal activity was recorded before compound exposure.
- Weighted mean firing rate (wMFR) was analyzed to identify compounds altering neuronal activity beyond a defined threshold.
Main Results:
- 54 out of 68 compounds in the first cohort and 13 out of 25 in the second cohort altered wMFR.
- MEAs detected 81.1% of compounds positive in NVS_IC assays.
- MEAs identified neurotoxicants not detected by NVS_IC assays, such as pyrethroids and GABAA antagonists, but showed insensitivity to most nicotinic compounds.
Conclusions:
- mwMEAs provide an efficient platform for screening chemical neurotoxicity.
- Results show good concordance with NVS_IC assays for ion channel interactions.
- MEAs offer complementary neurotoxicity detection, particularly for compounds affecting neuronal network activity differently than ion channel binding alone.
