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Cited by 35Genetics and Neurodevelopmental DisordersEpilepsy research and treatmentGenomic variations and chromosomal abnormalities

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

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Fink, James J., Schreiner, Jeremy D., Bloom, Judy E., James, Jadin, Baker, Dylan S., Robinson, Tiwanna M., Lieberman, Richard, Loew, Leslie M. +2 more·2021·Biological Psychiatry
DOI 10.1016/j.biopsych.2021.07.018PMC PMC8571044

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Abstract

Background 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, patients with Dup15q commonly meet the criteria for autism spectrum disorder and have a high prevalence of seizures. It is known from mouse models that synaptic impairments are a strong component of Dup15q pathophysiology; however, cellular phenotypes that relate to seizures are less clear. The development of patient-derived induced pluripotent stem cells provides a unique opportunity to study human neurons with the exact genetic disruptions that cause Dup15q. Methods Here, we explored electrophysiological phenotypes in induced pluripotent stem cell-derived neurons from 4 patients with Dup15q compared with 6 unaffected control subjects, 1 patient with a 15q11-q13 paternal duplication, and 3 patients with Angelman syndrome. Results We identified several properties of Dup15q neurons that could contribute to neuronal hyperexcitability and seizure susceptibility. Compared with control neurons, Dup15q neurons had increased excitatory synaptic event frequency and amplitude, increased density of dendritic protrusions, increased action potential firing, and decreased inhibitory synaptic transmission. 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 with control neurons, in part due to disruption of KCNQ2 potassium channels. Conclusions Together, these data point to multiple electrophysiological mechanisms of hyperexcitability that may provide new targets for the treatment of seizures and other phenotypes associated with Dup15q.

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  • Duplications and triplications of chromosomal region 15q11-q13, which increase UBE3A dosage, are strongly associated with non-syndromic ASD and epilepsy.

    “In contrast, duplications and triplications of the chromosomal region 15q11-q13, which increase UBE3A dosage, are strongly associated with non-syndromic ASD and epilepsy (Fink et al., 2021).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Fink et al., 2021

    The Introduction (page unavailable) says maternal 15q11-q13 duplications cause Dup15q and that affected patients commonly have ASD and a high prevalence of seizures. The Discussion (page unavailable) reports increased UBE3A expression in Dup15q patient-derived neurons. The paper describes this as a genetic syndrome, not non-syndromic ASD, and the cited passages do not establish the claim about triplications. (LLM, conf=0.89)

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  1. [1]Chamberlain SJ, Chen P-F, Ng KY, Bourgois-Rocha F, Lemtiri-Chlieh F, Levine ES, Lalande M (2010): Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proc Natl Acad Sci USA 107: 17668– 17673. 20876107 PMC2955112
  2. [2]Judson MC, Sosa-Pagan JO, Del Cid WA, Han JE, Philpot BD (2013): Allelic specificity of Ube3a expression in the mouse brain during postnatal development. J Comp Neurol 522: 1874– 1896. PMC3984624 24254964
  3. [3]Chamberlain SJ, Lalande M (2010): Neurodevelopmental disorders involving genomic imprinting at human chromosome 15q11-q13. Neurobiology of Disease 39: 13– 20. 20304067
  4. [4]Cassidy SB, Driscoll DJ (2008): Prader–Willi syndrome. European Journal of Human Genetics 17: 3. 18781185 PMC2985966
  5. [5]Chamberlain SJ, Lalande M (2010): Angelman syndrome, a genomic imprinting disorder of the brain. J Neurosci 30: 9958– 9963. 20668179 PMC6633366
  6. [6]Battaglia A (2005): The inv dup(15) or idic(15) syndrome: A clinically recognisable neurogenetic disorder. BRAIN AND DEVELOPMENT 27: 365– 369. 16023554
  7. [7]Kalsner L, Chamberlain SJ (2015): Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes. Pediatric Clinics of North America 62: 587– 606. 26022164 PMC4449422
  8. [8]Hogart A, Wu D, LaSalle JM, Schanen NC (2008): The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiology of Disease 38: 181– 191. 18840528 PMC2884398
  9. [10]Conant KD, Finucane B, Cleary N, Martin A, Muss C, Delany M, (2014): A survey of seizures and current treatments in 15q duplication syndrome. Epilepsia 55: 396– 402. 24502430
  10. [11]Friedman D, Thaler A, Thaler J, Rai S, Cook E, Schanen C, Devinsky O (2016): Mortality in isodicentric chromosome 15 syndrome: The role of SUDEP. Epilepsy Behav 61: 1– 5. 27218684
  11. [12]Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, (2009): Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11–13 Duplication Seen in Autism. Cell 137: Elsevier Inc. 1235– 1246. 19563756 PMC3710970
  12. [13]Smith SEP, Zhou Y-D, Zhang G, Jin Z, Stoppel DC, Anderson MP (2011): Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci Transl Med 3: 103ra97. PMC3356696 21974935
  13. [14]Krishnan V, Stoppel DC, Nong Y, Johnson MA, Nadler MJS, Ozkaynak E, (2017): Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. Nature 543: 507– 512. 28297715 PMC5364052
  14. [16]Piochon C, Kloth AD, Grasselli G, Titley HK, Nakayama H, Hashimoto K, (2014): Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nature Communications 5: 5586. PMC4243533 25418414
  15. [17]Chamberlain SJ, Chenb P-F, Ngb KY, Bourgois-Rochab F, Lemtiri-Chlieh F, Levinec ES, Lalande M (2010): Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader–Willi syndromes. PNAS 107: 17668– 17673. 20876107 PMC2955112
  16. [18]Chamberlain SJ, Li X-J, Lalande M (2008): Induced pluripotent stem (iPS) cells as in vitro models of human neurogenetic disorders. Neurogenetics 9: 227– 235. 18791750
  17. [20]Fink JJ, Robinson TM, Germain ND, Sirois CL, Bolduc KA, Ward AJ, (2017): Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells. Nature Communications 8: 15038. PMC5413969 28436452
  18. [22]Fink JJ, Levine ES (2018): Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders. Frontiers in Neurology. doi: 10.3389/fneur.2018.00237. PMC5911479 29713304 · DOI
  19. [23]Wallace ML, Burette AC, Weinberg RJ, Philpot BD (2012): Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron 74: 793– 800. 22681684 PMC3372864
  20. [24]Judson MC, Wallace ML, Sidorov MS, Burette AC, van Woerden GM, King IF, (2016): GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility. Neuron 90: 56– 69. 27021170 PMC4824651
  21. [25]Otmakhov N, Khibnik L, Otmakhova N, Carpenter S, Riahi S, Asrican B, Lisman J (2003): Forskolin-induced LTP in the CA1 hippocampal region is NMDA receptor dependent. Journal of Neurophysiology 91: 1955– 1962. 14702333
  22. [27]Pastuzyn ED, Shepherd JD (2017): Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome. Front Mol Neurosci 10: 234. 28804447 PMC5532393
  23. [28]Kühnle S, Mothes B, Matentzoglu K, Scheffner M (2013): Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proc Natl Acad Sci USA 110: 8888– 8893. 23671107 PMC3670309
  24. [29]Cao C, Rioult-Pedotti MS, Migani P, Yu CJ, Tiwari R, Parang K, (2013): Impairment of TrkB-PSD-95 signaling in Angelman syndrome. PLoS Biol 11: e1001478. 23424281 PMC3570550
  25. [30]Shepherd JD, Bear MF (2011): New views of Arc, a master regulator of synaptic plasticity. Nat Neurosci 14: 279– 284. 21278731 PMC8040377
  26. [31]Korb E, Finkbeiner S (2011): Arc in synaptic plasticity: from gene to behavior. Trends in Neurosciences 34: 591– 598. 21963089 PMC3207967
  27. [32]Turrigiano GG (2008): The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135: 422– 435. 18984155 PMC2834419
  28. [33]Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (1998): Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391: 892– 896. 9495341
  29. [34]Xu J-C, Fan J, Wang X, Eacker SM, Kam T-I, Chen L, (2016): Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci Transl Med 8: 333ra48. PMC5595216 27053772
  30. [36]Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (1998): Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391: 892– 896. 9495341
  31. [37]Maljevic S, Wuttke TV, Lerche H (2008): Nervous system KV7 disorders: breakdown of a subthreshold brake. The Journal of Physiology 586: 1791– 1801. 18238816 PMC2375730
  32. [38]Brown DA, Passmore GM (2009): Neural KCNQ (Kv7) channels. British Journal of Pharmacology 156: 1185– 1195. 19298256 PMC2697739
  33. [40]Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, (2010): The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140: 704– 716. 20211139 PMC2843143
  34. [41]Cao C, Rioult-Pedotti MS, Migani P, Yu CJ, Tiwari R, Parang K, (2013): Impairment of TrkB-PSD-95 Signaling in Angelman Syndrome. (Dalva M, editor.) PLoS Biol 11: e1001478. 23424281 PMC3570550
  35. [42]Jentsch TJ (2001): Neuronal KCNQ potassium channels: physiology and role in disease. Nat Rev Neurosci 1: 21– 30. 11252765
  36. [44]Nelson SB, Valakh V (2015): Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Neuron 87: 684– 698. 26291155 PMC4567857

Cited by

Sorted by citations

Authors
Fink, J. J., Schreiner, J. D., Bloom, J. E., James, J., Baker, D. S., Robinson, T. M., Lieberman, R., Loew, L. M., Chamberlain, S. J., & Levine, E. S.
Affiliations
University of Connecticut (US)
Corresponding author
Levine, Eric S.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2021-12
Volume
90
Issue
11
Pages
756-765
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2021.07.018
PMC
PMC8571044
OpenAlex
W3185145847
Cited by
35
References
9
Citations by year
2026: 5 · 2025: 10 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 1 · 2020: 3 · 2018: 1
FWCI
0.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (MH094896)
  • NINDS (NS078753, NS111965, NS111986)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
autism spectrum disorder, neuronal hyperexcitability, iPSC-derived neurons, seizure susceptibility, excitatory synaptic transmission, synaptic inhibition, dendritic protrusions, synaptic plasticity, synaptic scaling, Angelman syndrome
MeSH terms
Autism Spectrum Disorder, Animals, Autistic Disorder, Humans, Neurons, Phenotype, Mice, Induced Pluripotent Stem Cells

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