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Cited by 131Neuroscience and Neuropharmacology ResearchUbiquitin and proteasome pathwaysGenetics and Neurodevelopmental Disorders

UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

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Sun, Jiandong, Zhu, Guoqi, Liu, Yan, Standley, Steve, Ji, Angela, Tunuguntla, Rashmi, Wang, Yubin, Claus, Chad +3 more·2015·Cell Reports
DOI 10.1016/j.celrep.2015.06.023PMC PMC4520703
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Abstract

Gated solely by activity-induced changes in intracellular calcium, small-conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics, and Ca(2+) sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function.

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  • Gene Ontology sets for molecular function revealed no significant sets after Bonferroni correction for multiple testing.

    “analysis of Gene Ontology sets 81,82 for molecular function from MsigDB 83 revealed no significant sets after Bonferroni correction for multiple testing”

    From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [82]

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Cited by

Sorted by citations

Authors
Sun, J., Zhu, G., Liu, Y., Standley, S., Ji, A., Tunuguntla, R., Wang, Y., Claus, C., Luo, Y., Baudry, M., & Bi, X.
Affiliations
  • Western University of Health Sciences (US)
  • Anhui University of Traditional Chinese Medicine (CN)
Corresponding author
Bi, Xiaoning
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2015-07
Volume
12
Issue
3
Pages
449-461
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2015.06.023
PMC
PMC4520703
OpenAlex
W1547961772
Cited by
131
References
7
Citations by year
2026: 14 · 2025: 9 · 2024: 9 · 2023: 9 · 2022: 14 · 2021: 9 · 2020: 17 · 2019: 13 · 2018: 14 · 2017: 9 · 2016: 10 · 2015: 3
FWCI
5.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institute of Mental Health (MH101703, R15MH101703)
  • National Institute of Neurological Disorders and Stroke (P01NS045260, NS045260, NS057128, R01NS057128)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
UBE3A, small conductance calcium-activated potassium channels, SK2, synaptic plasticity, learning and memory, endocytosis, ubiquitination, Angelman syndrome, autism spectrum disorder, NMDA receptor activation, hippocampus, fear conditioning, postsynaptic localization, calcium signaling
MeSH terms
Animals, Chlorocebus aethiops, Cognition, Endocytosis, Learning, Male, Memory, Models, Molecular, Neuronal Plasticity, Transfection, COS Cells, Ubiquitin-Protein Ligases, Mice, Small-Conductance Calcium-Activated Potassium Channels

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