All-Optical Electrophysiology for High-Throughput Functional Characterization of a Human iPSC-Derived Motor Neuron Model of ALS

Stem Cell Reports
Evangelos KiskinisAdam E Cohen

Abstract

Human induced pluripotent stem cell (iPSC)-derived neurons are an attractive substrate for modeling disease, yet the heterogeneity of these cultures presents a challenge for functional characterization by manual patch-clamp electrophysiology. Here, we describe an optimized all-optical electrophysiology, "Optopatch," pipeline for high-throughput functional characterization of human iPSC-derived neuronal cultures. We demonstrate the method in a human iPSC-derived motor neuron (iPSC-MN) model of amyotrophic lateral sclerosis (ALS). In a comparison of iPSC-MNs with an ALS-causing mutation (SOD1 A4V) with their genome-corrected controls, the mutants showed elevated spike rates under weak or no stimulus and greater likelihood of entering depolarization block under strong optogenetic stimulus. We compared these results with numerical simulations of simple conductance-based neuronal models and with literature results in this and other iPSC-based models of ALS. Our data and simulations suggest that deficits in slowly activating potassium channels may underlie the changes in electrophysiology in the SOD1 A4V mutation.

Citations

Jun 5, 2019·Future Medicinal Chemistry·Juan Antonio Garcia-LeonAntonia Gutierrez
Jun 11, 2019·Expert Opinion on Drug Discovery·Jeremy W LinsleySteven Finkbeiner
Jan 21, 2020·Glia·Hélène HirbecCarole Escartin
Nov 7, 2019·Scientific Reports·Connor Beck, Yiyang Gong
Sep 29, 2020·Frontiers in Cell and Developmental Biology·Pedro Mateos-AparicioAntonio Rodríguez-Moreno
May 23, 2019·Journal of Neurophysiology·Colin K FranzEvangelos Kiskinis
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Feb 23, 2020·Molecular Autism·Wardiya Afshar Saber, Mustafa Sahin
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Software Mentioned

Optopatch
LabView
QuasAr2

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