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

Evangelos Kiskinis, Joel M. Kralj, Peng Zou, Eli N. Weinstein, Hongkang Zhang, Konstantinos Tsioras, Ole Wiskow, J. Alberto Ortega, Kevin Eggan*, Adam E. Cohen

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)1991-2004
Number of pages14
JournalStem cell reports
Volume10
Issue number6
DOIs
StatePublished - Jun 5 2018

Keywords

  • ALS
  • all-optical electrophysiology
  • iPSC
  • motor neurons

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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