The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery

Brick, David J.; Nethercott, Hubert E.; Montesano, Samantha; Bañuelos, Maria G.; Stover, Alexander E.; Schutte, Soleil S.; O’Dowd, Diane K.; Hagerman, Randi J.; Ono, Michele Y.; Hessl, David; Tassone, Flora; Schwartz, Philip H.

doi:10.5966/sctm.2014-0073erratum

Stem Cells Translational Medicine

2015

DOI: 10.5966/sctm.2014-0073erratum

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The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery

David J. Brick¹,

Hubert E. Nethercott²,

Samantha Montesano³

et al.

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“…Most significantly for models of neurodegeneration, diseaseassociated phenotypes have been seen to manifest in weeks in the context of in vitro cultures, in spite of the fact that the diseases may take decades to manifest in vivo. Third, there is growing interest in iPSC models of neuropsychiatric disorders, such as schizophrenia, bipolar, and autism spectrum disorders (8,22,31,36,39), where there is even greater emphasis on synaptic function and physiological endpoints.…”

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Forced cell cycle exit and modulation of GABA_A, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons

Telezhkin

Schnell

Yarova

et al. 2016

American Journal of Physiology-Cell Physiology

111

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Although numerous protocols have been developed for differentiation of neurons from a variety of pluripotent stem cells, most have concentrated on being able to specify effectively appropriate neuronal subtypes and few have been designed to enhance or accelerate functional maturity. Of those that have, most employ time courses of functional maturation that are rather protracted, and none have fully characterized all aspects of neuronal function, from spontaneous action potential generation through to postsynaptic receptor maturation. Here, we describe a simple protocol that employs the sequential addition of just two supplemented media that have been formulated to separate the two key phases of neural differentiation, the neurogenesis and synaptogenesis, each characterized by different signaling requirements. Employing these media, this new protocol synchronized neurogenesis and enhanced the rate of maturation of pluripotent stem cell-derived neural precursors. Neurons differentiated using this protocol exhibited large cell capacitance with relatively hyperpolarized resting membrane potentials; moreover, they exhibited augmented: 1) spontaneous electrical activity; 2) regenerative induced action potential train activity; 3) Na(+) current availability, and 4) synaptic currents. This was accomplished by rapid and uniform development of a mature, inhibitory GABAAreceptor phenotype that was demonstrated by Ca(2+) imaging and the ability of GABAAreceptor blockers to evoke seizurogenic network activity in multielectrode array recordings. Furthermore, since this protocol can exploit expanded and frozen prepatterned neural progenitors to deliver mature neurons within 21 days, it is both scalable and transferable to high-throughput platforms for the use in functional screens.

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mentioning

confidence: 99%

Forced cell cycle exit and modulation of GABA_A, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons

Telezhkin

Schnell

Yarova

et al. 2016

American Journal of Physiology-Cell Physiology

111

View full text Add to dashboard Cite

show abstract

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The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery

Cited by 1 publication

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Forced cell cycle exit and modulation of GABA_A, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons

Forced cell cycle exit and modulation of GABA_A, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons

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The Autism Spectrum Disorders Stem Cell Resource at Children's Hospital of Orange County: Implications for Disease Modeling and Drug Discovery

Cited by 1 publication

References 0 publications

Forced cell cycle exit and modulation of GABAA, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons

Forced cell cycle exit and modulation of GABAA, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons

Contact Info

Product

Resources

About

Forced cell cycle exit and modulation of GABA_A, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons

Forced cell cycle exit and modulation of GABA_A, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons