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In this study, we generated iPSC-derived neurons from AS patients and unaffected control subjects to compare the development of intrinsic excitability, action potential (AP) firing and excitatory synaptic activity and synaptic plasticity in these cells. The advent of induced pluripotent stem cell (iPSC) technology allows for the generation of patient-specific nervous tissue, which can be used to model a variety of neurological disorders 17. These data, in combination with findings of impaired synaptic plasticity, altered dendritic spines, and the cognitive and seizure phenotypes associated with these models 12, 13, 14, 15, 16, suggest that neurons from AS patients could have impairments in neuronal excitability and synaptic activity. Additionally, changes in intrinsic membrane properties and axon initial segment have also been reported in AS mouse models 10, 11. Moreover, the frequent seizure phenotype associated with AS could result from changes in neuronal excitability or disturbances to the balance of excitation and inhibition 9. Potential targets of UBE3A identified in mice include synaptic proteins such as EPHEXIN-5 and Arc 7, 8, suggesting that deficits in synaptic signalling may be involved in AS pathophysiology. The loss of ubiquitin ligase function in the neurons of patients with AS could cause the build-up of UBE3A target proteins that may contribute to disease pathogenesis 6. The UBE3A gene encodes an E3 ubiquitin ligase protein, also known as E6-associated protein, a molecule responsible for tagging target proteins for degradation by the proteasome. Therefore, the loss of the maternal allele of UBE3A results in the loss of UBE3A mRNA and protein in neurons 5. The paternal allele is silenced in these cells by the reciprocal expression of a long, non-coding antisense RNA 3. Due to genomic imprinting, UBE3A is solely expressed from the maternal allele in neurons.
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AS results from the loss of function of the UBE3A gene, a gene housed within this region. The 15q11–13 chromosomal region is regulated by genomic imprinting, an epigenetic phenomenon in which the expression of an allele is determined by the parent of origin. The prevalence of AS is estimated at 1/15,000 and is caused by the loss of the maternal 15q11–q13 chromosomal region 4.
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In addition, AS patients have been referred to as ‘Puppet children’ because these patients present with ataxia, happy affect and frequent bouts of laughter 1, 3. Our findings provide a cellular phenotype for investigating pathogenic mechanisms underlying AS and identifying novel therapeutic strategies.Īngelman syndrome (AS) is a neurodevelopmental disorder first described in 1965 by Harry Angelman and is characterized by developmental delay, language impairment, intellectual deficits and oftentimes, seizures 1, 2. 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. Importantly, these phenotypes could be rescued by pharmacologically unsilencing paternal UBE3A expression.
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These patient-specific differences were mimicked by knocking out UBE3A using CRISPR/Cas9 or by knocking down UBE3A using antisense oligonucleotides. AS-derived neurons showed impaired maturation of resting membrane potential and action potential firing, decreased synaptic activity and reduced synaptic plasticity. Here, we explored the underlying pathophysiology using induced pluripotent stem cell-derived neurons from AS patients and unaffected controls. 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.