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Nat Commun. 2017 Apr 24;8:15038. doi: 10.1038/ncomms15038.

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

Author information

1
Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, Connecticut 06030, USA.
2
Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, Connecticut 06030, USA.
3
Ionis Pharmaceuticals, Carlsbad, California 92010, USA.

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.

PMID:
28436452
PMCID:
PMC5413969
DOI:
10.1038/ncomms15038
[Indexed for MEDLINE]
Free PMC Article

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