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

• Published in: Stem cell reports Vol. 10; no. 6; pp. 1991 - 2004
• Main Authors: Kiskinis, Evangelos, Kralj, Joel M., Zou, Peng, Weinstein, Eli N., Zhang, Hongkang, Tsioras, Konstantinos, Wiskow, Ole, Ortega, J. Alberto, Eggan, Kevin, Cohen, Adam E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.06.2018; Elsevier
• Subjects: Action Potentials; all-optical electrophysiology; ALS; Amyotrophic Lateral Sclerosis; Biomarkers; Electrophysiological Phenomena; Gene Editing; Gene Expression; Humans; Induced Pluripotent Stem Cells - cytology; iPSC; Molecular Imaging; motor neurons; Motor Neurons - cytology; Motor Neurons - physiology; Mutation; Resource; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; motor neurons; ALS; all-optical electrophysiology; iPSC
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.04.020

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. [Display omitted] •All-optical electrophysiology enables high-throughput assays in hiPSC-derived neurons•Neurons derived from ALS patients fire differently from genome-corrected controls•A deficit in the Kv7 potassium current can explain the difference in firing In this article, Kiskinis and coworkers use all-optical electrophysiology to characterize an iPSC-based model of ALS. By performing high-throughput optical measurements of excitability in motor neurons derived from patients with a SOD1 (A4V) mutations and genome-corrected controls, the authors identify differences in firing consistent with a deficit in KV7 current in the mutants.