title: GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility.
abstract: Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Judson
authors.affiliation: Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Wallace
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sidorov
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Burette
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gu
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Geeske M
authors.initials: GM
authors.lastname: van Woerden
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: King
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Han
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Zylka
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands; ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
authors.forename: Ype
authors.initials: Y
authors.lastname: Elgersma
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weinberg
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: bphilpot@med.unc.edu.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Philpot
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D059330:GABAergic Neurons / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D019579:Neocortex / Q000378:metabolism* / Q000503:physiopathology; D009433:Neural Inhibition; D009474:Neurons / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism*; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018698:Glutamic Acid; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases