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Comparison of acute effects of neurotoxic compounds in neural networks from rodent and human neurons using microelectrode arrays
Citation:
Freudenrich, T., K. Wallace, D. Haag, L. Saavedra, W. Mundy, J. Davila, T. Sudof, M. Wernig, AND Tim Shafer. Comparison of acute effects of neurotoxic compounds in neural networks from rodent and human neurons using microelectrode arrays. Society of Toxicology 2017 Annual Meeting, Baltimore, Maryland, March 12 - 16, 2017.
Impact/Purpose:
this abstract compares neurotoxicity in rodent vs human neuronal cells and provides a scientific basis for beginning to utilize human cells for functional neurotoxicity screening
Description:
While neurotoxicity screening using neural networks derived from rodent tissue on microelectrode arrays (MEAs) is now routine, data from neural networks derived from human tissue is lacking. In the present study, we compared the activity of neural networks comprised of human neurons and glia derived from inducible pluripotent stem cells (iPSCs) to those from rat primary cortical cells. Human cells were plated onto 48 well MEA plates at the appropriate density and recordings were made using an Axion Maestro amplifier and software after 7, 14, 21, 28 and 35 days post plating (DPP). Developmental patterns of activity in the human networks were similar to that in rodent networks, beginning with poorly organized, individual spikes on early DPP (7-14) that progressed to coordinated network-wide bursting at later DPP (28-35). While similar in progression to activity in primary cortical networks derived from 0-24 hrs old rat pups, the ontogeny of network activity in iPSC-derived human neural cells matured more slowly than in rodent networks. To compare the effect of neurotoxic compounds, human and rodent networks were each treated acutely (1 hr) with bicuculline, glyphosate, tributyltin, lindane, deltamethrin and permethrin (0.1-30 µM). Cell viability was monitored using “in well” assays for lactate dehydrogenase (LDH) release and resazurin oxidation (Cell Titer Blue; CTB). The GABAA receptor blockers bicuculline and lindane each produced concentration-dependent increases in mean firing rate (MFR) in both human and rodent networks in the absence of cytotoxicity, while tributyltin decreased MFR and cell viability. Deltamethrin caused concentration-dependent decreases in MFR, while permethrin caused increases in MFR at low concentrations that returned to baseline at higher concentrations; neither deltamethrin nor permethrin caused changes in cell viability. Glyphosate was without effect on MFR or viability in rodent networks but increased MFR in human networks. However, this increase was not concentration-dependent. These results demonstrate that human neural networks consisting of neurons and glia derived from iPSCs demonstrate similar patterns of network spiking and bursting to rodent networks, but with a more prolonged ontogeny. Most important, the human- and rodent-derived networks responded similarly to a small set of neurotoxic compounds. Thus, these human neural networks are suitable for neurotoxicity screening. (This abstract does not represent EPA policy).