Ube3a is required for experience-dependent maturation of the neocortex
Open accessAbstract
Experience-dependent maturation of neocortical circuits is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. We tested whether experience-dependent neocortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in autism and Angelman syndrome. Using visual cortex as a model, we found that experience-dependent maturation of excitatory cortical circuits was severely impaired in Angelman syndrome model mice deficient in Ube3a. This developmental defect was associated with profound impairments in neocortical plasticity. Normal plasticity was preserved under conditions of sensory deprivation, but was rapidly lost by sensory experiences. The loss of neocortical plasticity is reversible, as late-onset visual deprivation restored normal synaptic plasticity. Furthermore, Ube3a-deficient mice lacked ocular dominance plasticity in vivo when challenged with monocular deprivation. We conclude that Ube3a is necessary for maintaining plasticity during experience-dependent neocortical development and suggest that the loss of neocortical plasticity contributes to deficits associated with Angelman syndrome.
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The Angelman syndrome mouse lacking maternal UBE3A has abnormal spine density on pyramidal neurons in the hippocampus and cortex.
“The Angelman syndrome mouse, which lacks the maternal UBE3A gene, displays motor deficits, impaired context-dependent learning, impaired plasticity and altered spine density on hippocampal and cortical pyramidal neurons45,85.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [85]
Experience-dependent maturation of excitatory circuits in the visual cortex is substantially impaired in maternal Ube3A deletion mice.
“Experience-dependent maturation of excitatory circuits in the visual cortex is substantially impaired in these same mice.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [91]
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 [91]
Sensory experience-regulated neocortical plasticity is defective in Ube3A mutant mice.
“In addition, sensory experience-regulated neocortical plasticity is defective in Ube3A mutant mice91.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [91]
In Ube3am−/p+ mice, maintenance of spine density after sensory stimulation is deficient.
“maintenance of spine density after sensory stimulation is deficient [196, 394]”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [394]
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References 50 · Cited by 328
- Authors
- 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.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Duke Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ehlers, Michael D
- Philpot, Benjamin D
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2009-05-10
- Volume
- 12
- Issue
- 6
- Pages
- 777-783
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2741303
- OpenAlex
- W2089542359
- Cited by
- 328
- References
- 50
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 13 · 2023: 10 · 2022: 8 · 2021: 19 · 2020: 24 · 2019: 17 · 2018: 18 · 2017: 23 · 2016: 18 · 2015: 22 · 2014: 22 · 2013: 31 · 2012: 31
- FWCI
- 17.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Howard Hughes Medical Institute
- Angelman Syndrome Foundation
- National Institutes of Health
- National Institute on Aging (AG024492, R01AG024492)
- National Eye Institute (R01EY018323)
- National Institute of Neurological Disorders and Stroke (NS039402, NS-035527, R01NS035527, R01NS039402)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32-HD-40127, T32HD040127)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- UBE3A, Angelman syndrome, visual cortex, synaptic plasticity, ocular dominance plasticity, monocular deprivation, sensory deprivation, autism spectrum disorder, E3 ubiquitin ligase, neurodevelopmental disorders
- MeSH terms
- Aging, Animals, Animals, Newborn, Cell Differentiation, Disease Models, Animal, Learning, Neuronal Plasticity, Sensory Deprivation, Visual Cortex, Visual Pathways, Visual Perception, Angelman Syndrome, Mice, Knockout, Neocortex, Dominance, Ocular, Ubiquitin-Protein Ligases, Mice
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