Defining an Electrophysiological Phenotype and Increasing Survival in Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive and almost universally fatal neurodegenerative disease of the human motor nervous system1. Multiple lines of evidence from ALS patients and animal models have suggested that intrinsic motor neuron hyperexcitability plays a key role in the disease2, but it has remained unclear whether this is a direct contributor to the early motor neuron cell death observed in ALS patients. We used motor neurons derived from induced pluripotent stem cells (iPSC) from ALS patients harboring one of three ALS-causing mutations and studied their electrophysiological properties using whole-cell patch-clamp and microelectrode array (MEA) single-unit activity. We indeed found ALS motor neurons were hyperexcitable at baseline relative to healthy controls, and determined this to be due to a reduction in delayed-rectifier potassium currents. We also found that this hyperexcitability directly contributes to the earlier cell death of ALS motor neurons in vitro. We then treated ALS motor neurons with the drug retigabine (currently an FDA- approved anticonvulsant drug), which is a Kv7 potassium channel activator, and found a reversal of this hyperexcitability as well as a normalization of cell life.