Pharmacological Profiling of Purified Human Stem Cell-Derived and Primary Mouse Motor Neurons

Directed differentiationof human pluripotent stem cells (hPSCs) has enabled the generation of specific neuronal subtypes that approximate the intended primary mammalian cells on both the RNA and protein levels. These cells offer unique opportunities, including insights into mechanistic understanding of the early driving events in neurodegenerative disease, replacement of degenerating cell populations, and compound identification and evaluation in the context of precision medicine. However, whether the derived neurons indeed recapitulate the physiological features of the desired bona fideneuronal subgroups remains an unanswered question and one important for validating stem cell models as accurate functional representationsof the primary celltypes. Here, we purified both hPSC-derived and primary mouse spinal motor neuronsin parallel and used extracellular multi- electrode array(MEA) recording to compare the pharmacological sensitivity of neuronal excitability and network function. We observed similar effects for most receptor and channel agonists and antagonists, supporting the consistency between human PSC-derived and mouse primary spinal motor neuronmodels from a physiological perspective.