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

Publication date: Available online 17 May 2018 Source:Stem Cell Reports Author(s): Evangelos Kiskinis, Joel M. Kralj, Peng Zou, Eli N. Weinstein, Hongkang Zhang, Konstantinos Tsioras, Ole Wiskow, J. Alberto Ortega, Kevin Eggan, Adam E. Cohen 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. Graphical abstract Teaser In this article, Kiskinis and coworkers use all-optical electrophysiology to characterize ...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research