Maternal Loss of Ube3a Produces an Excitatory/Inhibitory Imbalance through Neuron Type-Specific Synaptic Defects
Open accessAbstract
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A. AS model mice, which carry a maternal Ube3a null mutation (Ube3a(m-/p+)), recapitulate major features of AS in humans, including enhanced seizure susceptibility. Excitatory neurotransmission onto neocortical pyramidal neurons is diminished in Ube3a(m-/p+) mice, seemingly at odds with enhanced seizure susceptibility. We show here that inhibitory drive onto neocortical pyramidal neurons is more severely decreased in Ube3a(m-/p+) mice. This inhibitory deficit follows the loss of excitatory inputs and appears to arise from defective presynaptic vesicle cycling in multiple interneuron populations. In contrast, excitatory and inhibitory synaptic inputs onto inhibitory interneurons are largely normal. Our results indicate that there are neuron type-specific synaptic deficits in Ube3a(m-/p+) mice despite the presence of Ube3a in all neurons. These deficits result in excitatory/inhibitory imbalance at cellular and circuit levels and may contribute to seizure susceptibility in AS.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Inhibitory drive onto neocortical pyramidal neurons is impaired due to defective presynaptic vesicle cycling in interneuron populations.
“inhibitory drive onto neocortical pyramidal neurons is impaired owing to defective presynaptic vesicle cycling in interneuron populations92.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [92]
Excitatory drive onto neocortical pyramidal neurons is also diminished, but to a less severe extent.
“Excitatory drive onto neocortical pyramidal neurons is also diminished, but to a less severe extent92.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [92]
Ube3a protein regulates excitatory-inhibitory balance during brain development, and when its expression is perturbed ASD may occur.
“These studies suggest that Ube3a protein regulates excitatory–inhibitory balance during brain development and that when the level of expression is perturbed ASD may occur.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [92]
In Ube3am−/p+ mice, presynaptic GABA vesicle density is decreased at both inhibitory and excitatory synapses.
“presynaptic GABA vesicle density is decreased at both inhibitory and excitatory synapses [368].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [368]
In the visual cortex of Ube3am−/p+ mice, cell density of inhibitory interneurons is unaffected in layers II and III.
“cell density of inhibitory interneurons is unaffected in layers II and III [368]”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [368]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Interneurons of the neocortical inhibitory system
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1519 · Cited by 2,954 · see citing works
Model of autism: increased ratio of excitation/inhibition in key neural systems
Rubenstein, J. L. R., & Merzenich, M. M. (2003) · Genes, Brain and Behavior · doi:10.1034/j.1601-183x.2003.00037.x · Cited by 2,768 · see citing works
Driving fast-spiking cells induces gamma rhythm and controls sensory responses
Cardin, J. A., Carlén, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., Tsai, L.-H., & Moore, C. I. (2009) · Nature · doi:10.1038/nature08002 · Cited by 2,603 · see citing works
Critical period plasticity in local cortical circuits
Hensch, T. K. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1787 · Cited by 2,323 · see citing works
Decreased Hippocampal Inhibition and a Selective Loss of Interneurons in Experimental Epilepsy
Sloviter, R. S. (1987) · Science · doi:10.1126/science.2879352 · Cited by 1,082 · see citing works
Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex
Gupta, A., Wang, Y., & Markram, H. (2000) · Science · doi:10.1126/science.287.5451.273 · Cited by 1,036 · see citing works
A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice
Tabuchi, K., Blundell, J., Etherton, M. R., Hammer, R. E., Liu, X., Powell, C. M., & Südhof, T. C. (2007) · Science · doi:10.1126/science.1146221 · Cited by 997 · see citing works
Local GABA Circuit Control of Experience-Dependent Plasticity in Developing Visual Cortex
Hensch, T. K., Fagiolini, M., Mataga, N., Stryker, M. P., Baekkeskov, S., & Kash, S. F. (1998) · Science · doi:10.1126/science.282.5393.1504 · Cited by 910 · see citing works
Jiang, Y.-H., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., & Beaudet, A. L. (1998) · Neuron · doi:10.1016/s0896-6273(00)80596-6 · Cited by 852 · see citing works
Essential Role of Phosphoinositide Metabolism in Synaptic Vesicle Recycling
Cremona, O., Paolo, G. D., Wenk, M. R., Lüthi, A., Kim, W. T., Takei, K., DANIELL, L. W., Nemoto, Y., Shears, S. B., Flavell, R. A., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)81649-9 · Cited by 836 · see citing works
Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking
Chowdhury, S., Shepherd, J. D., Okuno, H., Lyford, G., Petralia, R. S., Plath, N., Kuhl, D., Huganir, R. L., & Worley, P. F. (2006) · Neuron · doi:10.1016/j.neuron.2006.08.033 · Cited by 792 · see citing works
Chaudhry, F. A., Reimer, R. J., Bellocchio, E. E., Danbolt, N. C., Osen, K. K., Edwards, R. H., & Storm‐Mathisen, J. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09733.1998 · Cited by 640 · see citing works
Dani, V. S., Chang, Q., Maffei, A., Turrigiano, G. G., Jaenisch, R., & Nelson, S. B. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506071102 · Cited by 639 · see citing works
Angelman syndrome 2005: Updated consensus for diagnostic criteria
Williams, C. A., Beaudet, A. L., Clayton‐Smith, J., Knoll, J. H. M., Kyllerman, M., Laan, L., Magenis, R. E., Moncla, A., Schinzel, A., Summers, J., et al. (2006) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.31074 · Cited by 626 · see citing works
Chattopadhyaya, B., Di Cristo, G., Higashiyama, H., Knott, G. W., Kuhlman, S. J., Welker, E., & Huang, Z. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1851-04.2004 · Cited by 596 · see citing works
Albrecht, U., Sutcliffe, J. S., Cattanach, B. M., BEECHEY, C. V., Armstrong, D. L., Gregor Eichele, C., & Beaudet, A. L. (1997) · Nature Genetics · doi:10.1038/ng0997-75 · Cited by 586 · see citing works
Gibson, J. R., Bartley, A. F., Hays, S. A., & Huber, K. M. (2008) · Journal of Neurophysiology · doi:10.1152/jn.90752.2008 · Cited by 529 · see citing works
Accessory factors in clathrin-dependent synaptic vesicle endocytosis
Slepnev, V. I., & Camilli, P. V. D. (2000) · Nature reviews. Neuroscience · doi:10.1038/35044540 · Cited by 517 · see citing works
The Angelman syndrome candidate gene, UBE3AIE6-AP, is imprinted in brain
Rougeulle, C., Glatt, H., & Lalande, M. (1997) · Nature Genetics · doi:10.1038/ng0997-14 · Cited by 416 · see citing works
Gonchar, Y. (2008) · Frontiers in Neuroanatomy · doi:10.3389/neuro.05.003.2007 · Cited by 369 · see citing works
Milošević, I., Giovedı̀, S., Lou, X., Raimondi, A., Collesi, C., Shen, H., Paradise, S., O'Toole, E. T., Ferguson, S. M., Cremona, O., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.08.029 · Cited by 351 · see citing works
Diversification of synaptic strength: presynaptic elements
Atwood, H. L., & Karunanithi, S. (2002) · Nature reviews. Neuroscience · doi:10.1038/nrn876 · Cited by 346 · see citing works
Dark Rearing Alters the Development of GABAergic Transmission in Visual Cortex
Morales, B., Choi, S.-Y., & Kirkwood, A. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-18-08084.2002 · Cited by 329 · see citing works
Ube3a is required for experience-dependent maturation of the neocortex
Yashiro, K., Riday, T. T., Condon, K. H., Roberts, A. C., Bernardo, D. R., Prakash, R., Weinberg, R. J., Ehlers, M. D., & Philpot, B. D. (2009) · Nature Neuroscience · doi:10.1038/nn.2327 · Cited by 328 · see citing works
Self-citationOkaty, B. W., Miller, M. N., Sugino, K., Hempel, C. M., & Nelson, S. B. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0105-09.2009 · Cited by 309 · see citing works
Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P., Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H.-Y. H., et al. (2010) · Cell · doi:10.1016/j.cell.2010.09.038 · Cited by 256 · see citing works
Cristo, G. D., Wu, C., Chattopadhyaya, B., Ango, F., Knott, G. W., Welker, E., Svoboda, K., & Huang, Z. J. (2004) · Nature Neuroscience · doi:10.1038/nn1334 · Cited by 161 · see citing works
Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation
McCurry, C. L., Shepherd, J. D., Tropea, D., Wang, K. H., Bear, M. F., & Sur, M. (2010) · Nature Neuroscience · doi:10.1038/nn.2508 · Cited by 159 · see citing works
Hayashi, M., Raimondi, A., O'Toole, E. T., Paradise, S., Collesi, C., Cremona, O., Ferguson, S. M., & Camilli, P. V. D. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712171105 · Cited by 152 · see citing works
Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a
Sato, M., & Stryker, M. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001281107 · Cited by 151 · see citing works
Thibert, R. L., Conant, K. D., Braun, E. K., Bruno, P. L., Said, R. R., Nespeca, M., & Thiele, E. A. (2009) · Epilepsia · doi:10.1111/j.1528-1167.2009.02108.x · Cited by 147 · see citing works
Jiang, B., Huang, S., Pasquale, R. D., Millman, D. J., Song, L., Lee, H., Tsumoto, T., & Kirkwood, A. (2010) · Neuron · doi:10.1016/j.neuron.2010.03.021 · Cited by 118 · see citing works
Angelman Syndrome Reviewed from a Neurophysiological Perspective. The UBE3A-GABRB3 Hypothesis
Dan, B., & Boyd, S. (2003) · Neuropediatrics · doi:10.1055/s-2003-42213 · Cited by 83 · see citing works
Lüthi, A., Paolo, G. D., Cremona, O., DANIELL, L. W., Camilli, P. V. D., & McCormick, D. A. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-23-09101.2001 · Cited by 56 · see citing works
The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc
Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T.-K., Griffith, E. C., Waldon, Z., Maehr, R., et al. (2010) · Cell · doi:10.1016/j.cell.2010.01.026 · Cited by 30 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Activity-dependent neuronal signalling and autism spectrum disorder
Ebert, D. H., & Greenberg, M. E. (2013) · Nature · doi:10.1038/nature11860 · Cited by 666 · see citing works
Autism spectrum disorder: neuropathology and animal models
Varghese, M., Keshav, N., Jacot-Descombes, S., Warda, T., Wicinski, B., Dickstein, D. L., Harony-Nicolas, H., De Rubeis, S., Drapeau, E., Buxbaum, J. D., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1736-4 · Cited by 536 · see citing works
Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders
Lee, E., Lee, J., & Kim, E. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.05.011 · Cited by 468 · see citing works
Antoine, M. W., Langberg, T., Schnepel, P., & Feldman, D. E. (2019) · Neuron · doi:10.1016/j.neuron.2018.12.026 · Cited by 413 · see citing works
An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A
Yi, J. J., Berrios, J., Newbern, J. M., Snider, W. D., Philpot, B. D., Hahn, K. M., & Zylka, M. J. (2015) · Cell · doi:10.1016/j.cell.2015.06.045 · Cited by 177 · see citing works
Self-citationLazaro, M. T., Taxidis, J., Shuman, T., Bachmutsky, I., Ikrar, T., Santos, R., Marcello, G. M., Mylavarapu, A., Chandra, S., Foreman, A., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.006 · Cited by 125 · see citing works
Coiro, P., Padmashri, R., Suresh, A., Spartz, E., Pendyala, G., Chou, S., Jung, Y., Meays, B., Roy, S., Gautam, N., et al. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.07.022 · Cited by 105 · see citing works
Rotaru, D. C., van Woerden, G. M., Wallaard, I., & Elgersma, Y. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.0083-18.2018 · Cited by 74 · see citing works
Kim, H., Kunz, P. A., Mooney, R., Philpot, B. D., & Smith, S. L. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.4204-15.2016 · Cited by 65 · see citing works
Self-citationMechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
Exposito-Alonso, D., & Rico, B. (2022) · Annual Review of Genetics · doi:10.1146/annurev-genet-072820-023642 · Cited by 49 · see citing works
Stem cells and modeling of autism spectrum disorders
Freitas, B. C. G., Trujillo, C. A., Carromeu, C., Yusupova, M., Herai, R. H., & Muotri, A. R. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2012.09.017 · Cited by 27 · see citing works
Enhanced Operant Extinction and Prefrontal Excitability in a Mouse Model of Angelman Syndrome
Sidorov, M. S., Judson, M. C., Kim, H., Rougie, M., Ferrer, A. I., Nikolova, V. D., Riddick, N. V., Moy, S. S., & Philpot, B. D. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2828-17.2018 · Cited by 25 · see citing works
Self-citationBhamidimarri, P. M., Alhosani, K., Cai, H., Al-Ali, H., Abukhaled, Y. M., Tawamie, H., Abdelaziz, S., Fawaz, M., Kashir, J., Sajjad, Y., et al. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107227 · Cited by 10 · see citing works
- Authors
- Wallace, M. L., Burette, A. C., Weinberg, R. J., & Philpot, B. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Philpot, Benjamin D.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 74
- Issue
- 5
- Pages
- 793-800
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3372864
- OpenAlex
- W2031215168
- Cited by
- 196
- References
- 35
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 21 · 2020: 23 · 2019: 14 · 2018: 15 · 2017: 15 · 2016: 17 · 2015: 15 · 2014: 12 · 2013: 14 · 2012: 1
- FWCI
- 8.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1f31ns077847-01)
- National Institute of Mental Health (R01MH093372)
- National Eye Institute (R01EY018323)
- National Institute of Neurological Disorders and Stroke (F31 NS077847, P30NS045892, R01NS035527, 1F31NS077847, T32NS007431)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30-HD03110, P30HD003110)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Angelman syndrome, UBE3A, excitatory-inhibitory imbalance, neocortical pyramidal neurons, interneurons, synaptic dysfunction, seizure susceptibility
- MeSH terms
- Age Factors, Animals, Animals, Newborn, Biophysics, Electric Stimulation, Mice, Transgenic, Nerve Net, Neural Inhibition, Neuronal Plasticity, Neurons, Parvalbumins, Somatostatin, Visual Cortex, Patch-Clamp Techniques, Gene Expression Regulation, Developmental, Ubiquitin-Protein Ligases, Green Fluorescent Proteins, Mice, Inhibitory Postsynaptic Potentials, S100 Calcium Binding Protein G, Calbindin 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
