Functional epilepsy modelling – a novel platform for studying human stem cell -derived neuronal networks
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1
University of Tampere, BioMediTech and Faculty of Medicine and Life Sciences, Finland
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2
Tampere University of Technology, Faculty of Biomedical Sciences and Engineering, Finland
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3
Tampere University of Technology, Faculty of Biomedical Sciences and Engineering, Finland
Motivation
Epilepsy is characterized by spread of abnormal electrical activity within and between neuronal networks. New epilepsy treatments are tested in rodent models, but less than 10 % of putative drugs are accepted for use[1] and 30 % of epilepsy patients still do not respond to existing treatments[2]. Therefore, new models are needed for epilepsy modelling and drug testing. Human pluripotent stem cell (hPSC) –derived neural networks are the most promising base material for such models, but they alone cannot model the connections, feedback loops and spread of abnormal activity between neuronal networks.
Material and Methods
Our solution is an innovative new platform which combines human stem cell –derived neural networks, microfluidic devices and microelectrode array (MEA) technology. hPSC–derived cortical neurons are cultured in the platform where they form functional networks. The networks are cultured in a microfluidic cell culture device which isolates the stem cell derived networks and the axonal connections between them. The device is comprised of polydimethylsiloxane (PDMS), and shaped using a micro- and millimeter-scale mold which consists of SU-8 and stainless steel (3D printed using selective laser melting (SLM)). The device is connected to a custom made MEA chip for measuring the electrical activity within and between the networks. The MEA chip is compatible with a commercially available MEA system (MEA2100, Multi Channel Systems, Reutlingen, Germany).
Results
The produced neuronal networks are highly active and respond to glutamatergic and GABAergic factors. The PDMS device allows the formation of axonal connections between separated neural networks. The PDMS device and the MEA chip are a suitable environment for the neural networks, which remained viable and active up to 12 weeks. The MEA data shows that the network activity in the device develops into synchronous, network-to-network connected bursts in 3-5 weeks. Individual networks can be subjected to seizure-inducing drugs, and the effects of the drug treatments are clearly visible in the MEA-data.
Conclusion
The platform is suitable for studying network activity and connectivity of human stem cell –derived neural networks. Therefore, it has the potential to be used in disease modelling and drug testing for epilepsy and other central nervous system disorders.
Acknowledgements
Funding: Business Finland (formerly known as Finnish Funding Agency for Technology and Innovation (TEKES)); Academy of Finland (Decision No. 311017); Finnish Cultural Foundation (personal grant, TR); Juliana von Wendt fund (personal grant, AP). The work was supported by the Imaging Facility, Facility of Electrophysiological Measurements and iPS Cells Facility (Uni. Tampere). Thanks to Arla Tanner for technical assistance and Juha Heikkilä for assistance with measurement and analysis software.
References
[1] Hay M, Thomas D W, Craighead J L, Economides C and Rosenthal J 2014 Clinical development success rates for investigational drugs Nat .Biotechnol . 32 40-51
[2] Loescher W 2016 Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies Epilepsy Res . 126 157-84
Keywords:
microelectrode array,
Microfluidics,
Polydimethylsiloxane,
Human pluripotent stem cells,
Epilepsy
Conference:
MEA Meeting 2018 | 11th International Meeting on Substrate Integrated Microelectrode Arrays, Reutlingen, Germany, 4 Jul - 6 Jul, 2018.
Presentation Type:
Poster Presentation
Topic:
Microphysiological systems
Citation:
Pelkonen
A,
Sukki
L,
Ryynänen
T,
Hyvärinen
T,
Lekkala
J,
Kallio
P and
Narkilahti
S
(2019). Functional epilepsy modelling – a novel platform for studying human stem cell -derived neuronal networks.
Conference Abstract:
MEA Meeting 2018 | 11th International Meeting on Substrate Integrated Microelectrode Arrays.
doi: 10.3389/conf.fncel.2018.38.00010
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Received:
16 Mar 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
PhD. Anssi Pelkonen, University of Tampere, BioMediTech and Faculty of Medicine and Life Sciences, Tampere, 33520, Finland, anssi.pelkonen@tuni.fi