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Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism

James J. Fink, Jeremy D. Schreiner, Judy E. Bloom, Dylan S. Baker, Tiwanna M. Robinson, Richard Lieberman, Leslie M. Loew, Stormy J. Chamberlain, Eric S. Levine
doi: https://doi.org/10.1101/286336
James J. Fink
1Dept. of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Jeremy D. Schreiner
1Dept. of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Judy E. Bloom
3R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Dylan S. Baker
1Dept. of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Tiwanna M. Robinson
1Dept. of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Richard Lieberman
1Dept. of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Leslie M. Loew
3R. D. Berlin Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Stormy J. Chamberlain
2Dept. of Genetics and Genome Sciences, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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Eric S. Levine
1Dept. of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030
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  • For correspondence: eslevine@uchc.edu
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Abstract

Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurogenetic disorder caused by duplications of the maternal copy of this region. In addition to hypotonia, motor deficits, and language impairments, Dup15q patients commonly meet the criteria for autism spectrum disorder (ASD) and have a high prevalence of seizures. Here, we explored mechanisms of hyperexcitability in neurons derived from induced pluripotent stem cell (iPSC) lines from Dup15q patients. Maturation of resting membrane potential in Dup15q-derived neurons was similar to neurons from unaffected control subjects, but Dup15q neurons had delayed action potential maturation and increased synaptic event frequency and amplitude. Dup15q neurons also showed impairments in activity-dependent synaptic plasticity and homeostatic synaptic scaling. Finally, Dup15q neurons showed an increased frequency of spontaneous action potential firing compared to control neurons, in part due to disruption of KCNQ2 channels. Together these data point to multiple mechanisms underlying hyperexcitability that may provide new targets for the treatment of seizures and other phenotypes associated with Dup15q.

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Posted March 21, 2018.
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Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism
James J. Fink, Jeremy D. Schreiner, Judy E. Bloom, Dylan S. Baker, Tiwanna M. Robinson, Richard Lieberman, Leslie M. Loew, Stormy J. Chamberlain, Eric S. Levine
bioRxiv 286336; doi: https://doi.org/10.1101/286336
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Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism
James J. Fink, Jeremy D. Schreiner, Judy E. Bloom, Dylan S. Baker, Tiwanna M. Robinson, Richard Lieberman, Leslie M. Loew, Stormy J. Chamberlain, Eric S. Levine
bioRxiv 286336; doi: https://doi.org/10.1101/286336

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