Hyperexcitable Phenotypes in Induced Pluripotent Stem Cell–Derived Neurons From Patients With 15q11-q13 Duplication Syndrome, a Genetic Form of Autism

Fink, James J.; Schreiner, Jeremy; Bloom, Judy E.; James, Jadin; Baker, Dylan; Robinson, Tiwanna M.; Lieberman, Richard; Loew, Leslie M.; Chamberlain, Stormy J.; Levine, Eric S.

doi:10.1016/j.biopsych.2021.07.018

Cited by 18 publications

(16 citation statements)

References 54 publications

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“…We used these lines to determine the functional differences between Dup15q and corrected neurons and investigate the role of UBE3A in Dup15q cellular phenotypes. Dup15q neurons exhibited multiple hyperexcitability phenotypes including an increase in voltage-gated inward current (and the associated increase in AP amplitude), decreased AP width, increased firing, and synaptic changes compared to isogenic corrected control neurons, consistent with previous findings (17).…”

Section: Discussionsupporting

confidence: 90%

“…Voltage-clamp recordings of Dup15q neurons and corrected isogenic controls revealed a significant increase in the frequency and amplitude of spontaneous excitatory postsynaptic currents at 19 weeks (sEPSCs; Fig. 3A), similar to our previous study comparing Dup15q lines to unaffected controls (17). There was also a decrease in the frequency, but not amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs; Fig.…”

Section: Altered Synaptic Transmission and Spontaneous Firing In Dup1...supporting

confidence: 88%

“…To study the consequences of UBE3A overexpression in the context of other duplicated genes in the region, and to confirm that the observed intrinsic excitability and synaptic phenotypes are modulated by UBE3A , we increased UBE3A dosage in an iPSC line with a paternal duplication in BP2-BP3 of the 11.2 to 13.1 region of chromosome 15 (PatDup). This line, which contains two silenced copies of UBE3A , was previously characterized and does not display Dup15q cellular phenotypes (17). UBE3A overexpression was achieved by using ASOs targeting UBE3A-ATS , a non-coding RNA that silences the paternal copy of UBE3A .…”

Section: Resultsmentioning

confidence: 99%

“…The H9 human embryonic stem cell line and an iPSC line from an unaffected individual were used as controls. These lines were previously characterized (7,17) and are available from the UConn Cell and Genome Engineering 13 Core. To create an isogenic corrected line, we began with an idic-1 clone that had also been transduced with a fluorescent reporter.…”

Section: Methodsmentioning

confidence: 99%

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The role ofUBE3Ain the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons

Elamin

Dumarchey

Stoddard

et al. 2022

Preprint

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Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q, but affected individuals also exhibit intellectual disability and developmental delay. UBE3A, the gene encoding the ubiquitin protein ligase E3A, is likely a major driver of Dup15q because individuals with maternal, but not paternal 15q duplications have the disorder, and UBE3A is the only imprinted gene expressed solely from the maternal allele in mature neurons. Nevertheless, the exact role of UBE3A is yet to be determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, UBE3A expression was manipulated in patient-derived induced pluripotent stem cell (iPSC) lines using antisense oligonucleotides. Dup15q neurons exhibited hyperexcitability features compared to genome-edited isogenic control neurons, and this phenotype was generally prevented by normalizing UBE3A levels throughout in vitro development. Overexpression of UBE3A in an iPSC line with a paternal duplication resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes. However, the inability of UBE3A overexpression to recapitulate synaptic phenotypes suggests an important role for non-imprinted genes in the disorder.

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Section: Discussionsupporting

confidence: 90%

Section: Altered Synaptic Transmission and Spontaneous Firing In Dup1...supporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The role ofUBE3Ain the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons

Elamin

Dumarchey

Stoddard

et al. 2022

Preprint

Self Cite

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“…This study found that 15q11-q13 duplication human neurons had overall heightened neuronal excitability and excitatory neurotransmission but reduced inhibitory neurotransmission, tipping the E/I balance. Similar to findings in the AS study, activity-dependent plasticity was absent in the 15q11-q13 duplication neurons ( Fink et al, 2021 ). Together these findings demonstrate disrupted electrophysiological properties and plasticity primarily in excitatory neurons carrying UBE3A patient mutations.…”

Section: Human In Vitro Model Recapitulating Epile...supporting

confidence: 86%

Modeling Epilepsy Using Human Induced Pluripotent Stem Cells-Derived Neuronal Cultures Carrying Mutations in Ion Channels and the Mechanistic Target of Rapamycin Pathway

Weng

Wang

2022

Front. Mol. Neurosci.

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Epilepsy is a neurological disorder that affects over 65 million people globally. It is characterized by periods of seizure activity of the brain as a result of excitation and inhibition (E/I) imbalance, which is regarded as the core underpinning of epileptic activity. Both gain- and loss-of-function (GOF and LOF) mutations of ion channels, synaptic proteins and signaling molecules along the mechanistic target of rapamycin (mTOR) pathway have been linked to this imbalance. The pathogenesis of epilepsy often has its roots in the early stage of brain development. It remains a major challenge to extrapolate the findings from many animal models carrying these GOF or LOF mutations to the understanding of disease mechanisms in the developing human brain. Recent advent of the human pluripotent stem cells (hPSCs) technology opens up a new avenue to recapitulate patient conditions and to identify druggable molecular targets. In the following review, we discuss the progress, challenges and prospects of employing hPSCs-derived neural cultures to study epilepsy. We propose a tentative working model to conceptualize the possible impact of these GOF and LOF mutations in ion channels and mTOR signaling molecules on the morphological and functional remodeling of intrinsic excitability, synaptic transmission and circuits, ultimately E/I imbalance and behavioral phenotypes in epilepsy.

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IPSC Models of Chromosome 15Q Imprinting Disorders: From Disease Modeling to Therapeutic Strategies

Germain

Levine

Chamberlain

2020

Advances in Neurobiology

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Hyperexcitable Phenotypes in Induced Pluripotent Stem Cell–Derived Neurons From Patients With 15q11-q13 Duplication Syndrome, a Genetic Form of Autism

Cited by 18 publications

References 54 publications

The role ofUBE3Ain the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons

The role ofUBE3Ain the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons

Modeling Epilepsy Using Human Induced Pluripotent Stem Cells-Derived Neuronal Cultures Carrying Mutations in Ion Channels and the Mechanistic Target of Rapamycin Pathway

IPSC Models of Chromosome 15Q Imprinting Disorders: From Disease Modeling to Therapeutic Strategies

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