title: UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis.
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.
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Traditional Chinese Medicine, Hefei 230038, China.
authors.forename: Guoqi
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Standley
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Ji
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Tunuguntla
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Claus
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
authors.affiliation: Western University of Health Sciences, Pomona, CA 91766, USA. Electronic address: xbi@westernu.edu.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Bi
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003071:Cognition / Q000502:physiology; D004705:Endocytosis; D007858:Learning / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D009473:Neuronal Plasticity / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: C496897:KCNN2 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases