Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells

James J. Fink, Tiwanna M. Robinson, Noelle D. Germain, Carissa L. Sirois, Kaitlyn A. Bolduc, Amanda J. Ward, Frank Rigo, Stormy J. Chamberlain and Eric S. Levine ()
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James J. Fink: University of Connecticut School of Medicine
Tiwanna M. Robinson: University of Connecticut School of Medicine
Noelle D. Germain: University of Connecticut School of Medicine
Carissa L. Sirois: University of Connecticut School of Medicine
Kaitlyn A. Bolduc: University of Connecticut School of Medicine
Amanda J. Ward: Ionis Pharmaceuticals
Frank Rigo: Ionis Pharmaceuticals
Stormy J. Chamberlain: University of Connecticut School of Medicine
Eric S. Levine: University of Connecticut School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Angelman syndrome (AS) is a neurogenetic disorder caused by deletion of the maternally inherited UBE3A allele and is characterized by developmental delay, intellectual disability, ataxia, seizures and a happy affect. Here, we explored the underlying pathophysiology using induced pluripotent stem cell-derived neurons from AS patients and unaffected controls. AS-derived neurons showed impaired maturation of resting membrane potential and action potential firing, decreased synaptic activity and reduced synaptic plasticity. These patient-specific differences were mimicked by knocking out UBE3A using CRISPR/Cas9 or by knocking down UBE3A using antisense oligonucleotides. Importantly, these phenotypes could be rescued by pharmacologically unsilencing paternal UBE3A expression. Moreover, selective effects of UBE3A disruption at late stages of in vitro development suggest that changes in action potential firing and synaptic activity may be secondary to altered resting membrane potential. Our findings provide a cellular phenotype for investigating pathogenic mechanisms underlying AS and identifying novel therapeutic strategies.

Date: 2017
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DOI: 10.1038/ncomms15038

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