Skip to main content

Addressing Functional Neurotoxicity Using the Microelectrode Array (MEA)

Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Early drug development requires tests for compound-induced neurotoxic effects, i.e., to investigate possible alterations of neuronal activity as a result of the test compound. In vivo and in vitro animal models transpire not to be overly predictive of neurotoxic effects in humans and furthermore are in contradiction to the efforts of the European Community to reduce the number of animal experiments. Consequently, alternatives to these animal model-based assays are currently being investigated. Human induced pluripotent stem cell (hiPSC)-derived neurons offer several advantages, including being of human origin and offering the possibility of developing disease models from patient-derived cells. The development of electrophysiological assays based on microelectrode array systems (MEA) allows one to study alterations of neuronal activity in samples of varying complexity ranging from single cells to neuronal networks. As a non-invasive method it supports not only acute but also long-term experiments for extended time periods. Here we describe how to record neuronal activity from neurons and provide exemplarily insights into a validation study for a commercially available hiPSC-derived neuronal cell type.

Key words

  • Microelectrode array
  • MEA
  • Multi-well
  • Assay development
  • Spike analysis
  • Neuronal activity
  • Threshold detection

This is a preview of subscription content, access via your institution.

Buying options

Protocol
USD   49.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-6661-5_15
  • Chapter length: 17 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   109.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-6661-5
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   139.00
Price excludes VAT (USA)
Hardcover Book
USD   169.99
Price excludes VAT (USA)
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Dragunow M (2008) The adult human brain in preclinical drug development. Nat Rev Drug Discov 7:659–666. doi:10.1038/nrd2617

    CAS  CrossRef  PubMed  Google Scholar 

  2. Peitz M, Jungverdorben J, Brustle O (2013) Disease-specific iPS cell models in neuroscience. Curr Mol Med 13:832–841. doi:10.2174/1566524011313050014

    CAS  CrossRef  PubMed  Google Scholar 

  3. Imaizumi Y, Okano H (2014) Modeling human neurological disorders with induced pluripotent stem cells. J Neurochem 129:388–399. doi:10.1111/jnc.12625

    CAS  CrossRef  PubMed  Google Scholar 

  4. Vassos E, Collier DA, Holden S et al (2010) Penetrance for copy number variants associated with schizophrenia. Hum Mol Genet 19:3477–3481. doi:10.1093/hmg/ddq259

    CAS  CrossRef  PubMed  Google Scholar 

  5. Thomas CA, Springer PA, Loeb GE et al (1972) A miniature microelectrode array to monitor the bioelectric activity of cultured cells. Exp Cell Res 74:61–66. doi:10.1016/0014-4827(72)90481-8

  6. Potter SM (2001) Distributed processing in cultured neuronal networks. Prog Brain Res 130:49–62

    CAS  CrossRef  PubMed  Google Scholar 

  7. Stett A, Egert U, Guenther E et al (2003) Biological application of microelectrode arrays in drug discovery and basic research. Anal Bioanal Chem 377:486–495. doi:10.1007/s00216-003-2149-x

    CAS  CrossRef  PubMed  Google Scholar 

  8. Peri.4U – hiPSC Peripheral Neurons - AXIOGENESIS - iPSC Human Cardiomyocytes Neurons Hypertrophy Disease Model Cells. http://axiogenesis.com/products/neuronal-cells/peri-4u-hipsc-peripheral-neurons.html. Accessed 25 Feb 2016

  9. Nyquest H (1928) Certain topics in telegraph transmission theory. Trans Am Inst Electr Eng 47:617–644

    CrossRef  Google Scholar 

  10. Holt GR, Koch C (1999) Electrical interactions via the extracellular potential near cell bodies. J Comput Neurosci 6:169–184. doi:10.1023/A:1008832702585

    CAS  CrossRef  PubMed  Google Scholar 

  11. Buzsáki G, Anastassiou CA, Koch C (2012) The origin of extracellular fields and currents—EEG, ECoG, LFP and spikes. Nat Rev Neurosci 13:407–420. doi:10.1038/nrn3241

    CrossRef  PubMed  PubMed Central  Google Scholar 

  12. Canepari M, Bove M, Maeda E et al (1997) Experimental analysis of neuronal dynamics in cultured cortical networks and transitions between different patterns of activity. Biol Cybern 77:153–162. doi:10.1007/s004220050376

    CAS  CrossRef  PubMed  Google Scholar 

  13. Morefield SI, Keefer EW, Chapman KD, Gross GW (2000) Drug evaluations using neuronal networks cultured on microelectrode arrays. Biosens Bioelectron 15:383–396. doi:10.1016/S0956-5663(00)00095-6

    CAS  CrossRef  PubMed  Google Scholar 

  14. Quiroga RQ, Nadasdy Z, Ben-Shaul Y (2004) Unsupervised spike detection and sorting with wavelets and superparamagnetic clustering. Neural Comput 16:1661–1687. doi:10.1162/089976604774201631

    CrossRef  PubMed  Google Scholar 

  15. Muthmann J-O, Amin H, Sernagor E et al (2015) Spike detection for large neural populations using high density multielectrode arrays. Front Neuroinform 9:28. doi:10.3389/fninf.2015.00028

    CrossRef  PubMed  PubMed Central  Google Scholar 

  16. Ness TV, Chintaluri C, Potworowski J et al (2015) Modelling and analysis of electrical potentials recorded in microelectrode arrays (MEAs). Neuroinformatics 13:403–426. doi:10.1007/s12021-015-9265-6

    CrossRef  PubMed  PubMed Central  Google Scholar 

  17. Defranchi E, Novellino A, Whelan M et al (2011) Feasibility assessment of micro-electrode chip assay as a method of detecting neurotoxicity in vitro. Front Neuroeng 4:6. doi:10.3389/fneng.2011.00006

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  18. Singh AN, Barlas C, Singh S et al (1996) A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes. J Psychiatry Neurosci 21:29–35

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kapur S, Zipursky R, Remington G et al (1997) PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia. Am J Psychiatry 154:1525–1529. doi:10.1176/ajp.154.11.1525

    CAS  CrossRef  PubMed  Google Scholar 

  20. Kinney JL (1985) Nomifensine maleate: a new second-generation antidepressant. Clin Pharm 4:625–636

    CAS  PubMed  Google Scholar 

  21. Fiedorowicz A, Figiel I, Kamińska B et al (2001) Dentate granule neuron apoptosis and glia activation in murine hippocampus induced by trimethyltin exposure. Brain Res 912:116–127. doi:10.1016/S0006-8993(01)02675-0

    CAS  CrossRef  PubMed  Google Scholar 

  22. Cho JS, Kim TH, Lim J-M, Song J-H (2008) Effects of eugenol on Na+ currents in rat dorsal root ganglion neurons. Brain Res 1243:53–62. doi:10.1016/j.brainres.2008.09.030

    CAS  CrossRef  PubMed  Google Scholar 

  23. Moreira-Lobo DCA, Linhares-Siqueira ED, Cruz GMP et al (2010) Eugenol modifies the excitability of rat sciatic nerve and superior cervical ganglion neurons. Neurosci Lett 472:220–224. doi:10.1016/j.neulet.2010.02.009

    CAS  CrossRef  PubMed  Google Scholar 

  24. Lindstrom J (1997) Nicotinic acetylcholine receptors in health and disease. Mol Neurobiol 15:193–222. doi:10.1007/BF02740634

    CAS  CrossRef  PubMed  Google Scholar 

  25. Yoshida T, Sakane N, Umekawa T, Kondo M (1994) Effect of nicotine on sympathetic nervous system activity of mice subjected to immobilization stress. Physiol Behav 55:53–57. doi:10.1016/0031-9384(94)90009-4

    CAS  CrossRef  PubMed  Google Scholar 

  26. Sewell RG, Nanry KP, Kennedy J et al (1985) Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole. Pharmacol Biochem Behav 22:469–477

    CAS  CrossRef  PubMed  Google Scholar 

  27. Chen K, Wang J-J, Yung WH et al (2005) Excitatory effect of histamine on neuronal activity of rat globus pallidus by activation of H2 receptors in vitro. Neurosci Res 53:288–297. doi:10.1016/j.neures.2005.07.008

    CAS  CrossRef  PubMed  Google Scholar 

  28. Zhang J, Han X-H, Li H-Z et al (2008) Histamine excites rat lateral vestibular nuclear neurons through activation of post-synaptic H2 receptors. Neurosci Lett 448:15–19. doi:10.1016/j.neulet.2008.10.027

    CAS  CrossRef  PubMed  Google Scholar 

  29. EFSA (2008) Conclusion regarding the peer review of the pesticide risk assessment of the active substance mepiquat. EFSA Journal 6(7). http://dx.doi.org/10.2903%2Fj.efsa.2008.146r

Download references

Acknowledgements

Parts of the research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115439, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. This publication reflects only the author’s views and neither the IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Udo Kraushaar .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this protocol

Cite this protocol

Kraushaar, U., Guenther, E., Hess, D. (2017). Addressing Functional Neurotoxicity Using the Microelectrode Array (MEA). In: Clements, M., Roquemore, L. (eds) Stem Cell-Derived Models in Toxicology. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6661-5_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6661-5_15

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6659-2

  • Online ISBN: 978-1-4939-6661-5

  • eBook Packages: Springer Protocols