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
Jan 10, 2020·Stem Cell Reviews and Reports·Andong ZhaoSa Cai
Aug 14, 2020·American Journal of Physiology. Cell Physiology·Masood Sepehrimanesh, Baojin Ding
Sep 29, 2020·Frontiers in Cell and Developmental Biology·Pedro Mateos-AparicioAntonio Rodríguez-Moreno
May 23, 2019·Journal of Neurophysiology·Colin K FranzEvangelos Kiskinis
May 24, 2019·Frontiers in Cellular Neuroscience·Vishalini EmmeneggerAndreas Hierlemann
Sep 8, 2020·Military Medical Research·An-Dong ZhaoXiao-Bing Fu
Feb 23, 2020·Molecular Autism·Wardiya Afshar Saber, Mustafa Sahin
Nov 5, 2020·Nature Communications·Michael ZabolockiCedric Bardy
Jan 30, 2021·Frontiers in Neuroscience·Austin P Passaro, Steven L Stice
Feb 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Therese C AlichIstvan Mody
Apr 17, 2021·Nature Chemistry·Shuzhang LiuPeng Zou
Apr 24, 2021·Neuroscience Letters·Laura Ferraiuolo, Nicholas J Maragakis
Apr 6, 2021·Photochemistry and Photobiology·Gaoxiang MeiKenneth J Rothschild
Jun 15, 2021·Frontiers in Cellular Neuroscience·Francesca PuppoAnna Devor
Aug 11, 2021·Journal of Neuroscience Methods·Daria M Shcherbakova
Sep 3, 2021·Journal of Molecular Biology·Matthew Tegtmeyer, Ralda Nehme
Oct 30, 2021·Frontiers in Genome Editing·Amy McTagueManju A Kurian