title: Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model.
abstract: Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal UBE3A gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular mechanisms whereby Ube3a deficiency results in AS are enigmatic. Using in vitro and in vivo systems we show dramatic changes in the expression of Ube3a following synaptic activation. In primary neuronal culture, neuronal depolarization was found to increase both nuclear and cytoplasmic Ube3a levels. Analogous up-regulation in maternal and paternal Ube3a expression was observed in Ube3a-YFP reporter mice following fear conditioning. Absence of Ube3a led to deficits in the activity-dependent increases in ERK1/2 phosphorylation, which may contribute to reported deficits in synaptic plasticity and cognitive function in AS mice. Taken together, our findings provide novel insight into the regulation of Ube3a by synaptic activity and its potential role in kinase regulation.
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Byrd Alzheimer's Institute, Tampa, Florida 33613, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Filonova
authors.forename: Justin H
authors.initials: JH
authors.lastname: Trotter
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Banko
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
mesh_terms: D017204:Angelman Syndrome / Q000201:enzymology / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003213:Conditioning, Psychological; D003593:Cytoplasm / Q000378:metabolism; D005239:Fear / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D010290:Parents; D009435:Synaptic Transmission; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases