title: Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.
abstract: Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the UBE3A gene encoding a ubiquitin E3 ligase. Motor dysfunction is a characteristic feature of Angelman syndrome, but neither the mechanisms of action nor effective therapeutic strategies have yet been elucidated. We report that tonic inhibition is specifically decreased in cerebellar granule cells of Ube3a-deficient mice, a model of Angelman syndrome. As a mechanism underlying this decrease in tonic inhibition, we show that Ube3a controls degradation of γ-aminobutyric acid (GABA) transporter 1 (GAT1) and that deficiency of Ube3a induces a surplus of GAT1 that results in a decrease in GABA concentrations in the extrasynaptic space. Administering low doses of 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP), a selective extrasynaptic GABA(A) receptor agonist, improves the abnormal firing properties of a population of Purkinje cells in cerebellar brain slices and reduces cerebellar ataxia in Ube3a-deficient mice in vivo. These results suggest that pharmacologically increasing tonic inhibition may be a useful strategy for alleviating motor dysfunction in Angelman syndrome.
authors.affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan. cdh67560@par.odn.ne.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Egawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takayama
authors.forename: Chitoshi
authors.initials: C
authors.lastname: Takayama
authors.forename: Shinji
authors.initials: S
authors.lastname: Saitoh
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kishino
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
mesh_terms: D017204:Angelman Syndrome / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D004195:Disease Models, Animal; D018755:GABA Agonists / Q000494:pharmacology / Q000627:therapeutic use; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D007555:Isoxazoles; D005680:gamma-Aminobutyric Acid; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; C015542:gaboxadol