Multielectrode array recordings of human iPSC-derived neurons reveal differences in network activity depending on differentiation protocol and genome modification

Abstract

Event Abstract Back to Event Multielectrode array recordings of human iPSC-derived neurons reveal differences in network activity depending on differentiation protocol and genome modification Sandra K. Fischer1* and Frank Gillardon1 1 Boehringer Ingelheim (Germany), Germany With increasing prevalence of neuropsychiatric disorders, there is an ever-growing need for suitable model systems to understand the underlying pathological mechanisms. Currently most data are derived from animal models, although correlations between animal and human are often weak. However, acquisition of human neuronal material is rarely possible and afflicted with ethic concerns. Human induced pluripotent stem cell (hiPSC) derived neuronal cultures offer a possibility to overcome these limitations. Synaptic activity and neurotransmission deficits have been identified as core pathophysiologies of neuropsychiatric disorders. The multi electrode array (MEA) technology allows for repeated measurements of electrical activity of functional neuronal networks over an extended period of time. We cultivated iPSC-derived neuronal cultures on the Multichannel Systems MEA multiwell platform and assessed synaptic activity over time and in response to treatment with pharmacological agents. The hiPSC-derived neurons developed electrical activity from single spikes to bursts over time indicating maturation. Dot-seeded GlutaNeurons (iCell Neurons, Cellular Dynamics International) showed their peak activity after 2-3 weeks in culture with the highest burst activity in week 3. Ngn2-induced Neurons (iCell Neurons, Cellular Dynamics International) displayed a weaker total activity with lower spike rate, less burst activity and a maximum activity after 6 weeks in culture. Treatment with the GABA antagonist Bicuculline evoked synchronized burst firing in GlutaNeuron cultures containing approx. 20% GABAergic neurons, whereas the spontaneous activity of the purely glutamatergic culture of Induced Neurons was unchanged as expected. Loss-of-function mutations in ErbB receptor tyrosine kinases have been identified as genetic risk factors for neuropsychiatric diseases. Upon pharmacological inhibition of ErbB receptor tyrosine kinases, neuronal network activity was inhibited, consistent with our MEA recordings from primary rat cortical neuron cultures. Moreover, we generated a loss-of-function mutation in a high risk gene for schizophrenia in hiPSC from a healthy donor utilizing the CRISPR/Cas9 gene editing system. Following neuronal differentiation into the forebrain lineage electrophysiological activity was monitored on the MEA multiwell system during network formation and maturation. Preliminary data indicate altered spontaneous network activity in mutant iPSC-derived neurons compared to isogenic controls. In summary, our findings demonstrate that hiPSC-derived neurons form functional neuronal networks on MEA plates which can serve as suitable system for modeling of neuropsychiatric diseases. Acknowledgements The authors thank Dr. Sabine Lange (Cellular Dynamics International) for helpful discussions. Keywords: IPSC-derived neurons, neuropsychiatric disorder, electrical network activity, multielectrode array plate, CRISPR/Cas9 gene editing Conference: MEA Meeting 2018 | 11th International Meeting on Substrate Integrated Microelectrode Arrays, Reutlingen, Germany, 4 Jul - 6 Jul, 2018. Presentation Type: Poster Presentation Topic: Stem cell-derived applications Citation: Fischer SK and Gillardon F (2019). Multielectrode array recordings of human iPSC-derived neurons reveal differences in network activity depending on differentiation protocol and genome modification. Conference Abstract: MEA Meeting 2018 | 11th International Meeting on Substrate Integrated Microelectrode Arrays. doi: 10.3389/conf.fncel.2018.38.00015 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Mar 2018; Published Online: 17 Jan 2019. * Correspondence: Mrs. Sandra K Fischer, Boehringer Ingelheim (Germany), Hannover, Germany, sandra.fischer@boehringer-ingelheim.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sandra K Fischer Frank Gillardon Google Sandra K Fischer Frank Gillardon Google Scholar Sandra K Fischer Frank Gillardon PubMed Sandra K Fischer Frank Gillardon Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.