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Stimulation of GABA-induced Ca2+ influx enhances maturation of human induced pluripotent stem cell-derived neurons

Rushton, David J., Mattis, Virginia B., Svendsen, Clive N., Allen, Nicholas Denby and Kemp, Paul J. 2013. Stimulation of GABA-induced Ca2+ influx enhances maturation of human induced pluripotent stem cell-derived neurons. PLoS ONE 8 (11) , e81031. 10.1371/journal.pone.0081031

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Abstract

Optimal use of patient-derived, induced pluripotent stem cells for modeling neuronal diseases is crucially dependent upon the proper physiological maturation of derived neurons. As a strategy to develop defined differentiation protocols that optimize electrophysiological function, we investigated the role of Ca2+ channel regulation by astrocyte conditioned medium in neuronal maturation, using whole-cell patch clamp and Ca2+ imaging. Standard control medium supported basic differentiation of induced pluripotent stem cell-derived neurons, as assayed by the ability to fire simple, single, induced action potentials. In contrast, treatment with astrocyte conditioned medium elicited complex and spontaneous neuronal activity, often with rhythmic and biphasic characteristics. Such augmented spontaneous activity correlated with astrocyte conditioned medium-evoked hyperpolarization and was dependent upon regulated function of L-, N- and R-type Ca2+ channels. The requirement for astrocyte conditioned medium could be substituted by simply supplementing control differentiation medium with high Ca2+ or γ-amino butyric acid (GABA). Importantly, even in the absence of GABA signalling, opening Ca2+ channels directly using Bay K8644 was able to hyperpolarise neurons and enhance excitability, producing fully functional neurons. These data provide mechanistic insight into how secreted astrocyte factors control differentiation and, importantly, suggest that pharmacological modulation of Ca2+ channel function leads to the development of a defined protocol for improved maturation of induced pluripotent stem cell-derived neurons.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 06:21
URI: http://orca-mwe.cf.ac.uk/id/eprint/59032

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