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The effect of rho kinase inhibition on morphological and electrophysiological maturity in iPSC-derived neurons

Harbom, Lise J., Rudisill, Taylor L., Michel, Nadine, Litwa, Karen A., Beenhakker, Mark P., McConnell, Michael J.
Cell and tissue research 2019 v.375 no.3 pp. 641-654
adults, enzyme inhibition, enzymes, humans, membrane potential, models, nervous system diseases, neurites, neurogenesis
Induced pluripotent stem cell (iPSC)-derived neurons permit the study of neurogenesis and neurological disease in a human setting. However, the electrophysiological properties of iPSC-derived neurons are consistent with those observed in immature cortical neurons, including a high membrane resistance depolarized resting membrane potential and immature firing properties, limiting their use in modeling neuronal activity in adult cells. Based on the proven association between inhibiting rho kinase (ROCK) and increased neurite complexity, we seek to determine if short-term ROCK inhibition during the first 1–2 weeks of differentiation would increase morphological complexity and electrophysiological maturity after several weeks of differentiation. While inhibiting ROCK resulted in increased neurite formation after 24 h, this effect did not persist at 3 and 6 weeks of age. Additionally, there was no effect of ROCK inhibition on electrophysiological properties at 2–3, 6, or 12 weeks of age, despite an increase in evoked and spontaneous firing and a more hyperpolarized resting membrane potential over time. These results indicate that while there is a clear effect of time on electrophysiological maturity, ROCK inhibition did not accelerate maturity.