title: Heterozygous mice deficient in Atp1a3 exhibit motor deficits by chronic restraint stress.
abstract: Dystonia is a neurological disorder with involuntary and simultaneous contractions of agonist and antagonist muscles. Rapid-onset dystonia parkinsonism (RDP), one of the heredity forms of dystonia, is caused by mutations of Na,K-ATPase α3 subunit gene (ATP1A3). The abrupt onset of bulbar and limb symptoms of RDP are often triggered by physical and/or emotional stress. We reported previously that Atp1a3-deficient heterozygous mice showed higher locomotor activity and developed enhanced dystonia symptoms after kainate injection into the cerebellum, but not spontaneous movement disorder like RDP patients. Here we show that Atp1a3-deficient heterozygous mice exhibited shorter stride length at 4 weeks of age without stress and at later stages under chronic restraint stress loading. Shorter hanging time in the hanging box test was also observed after stress loading. Shorter stride length and hanging time may be relevant to certain phenotypes, such as gait abnormality, observed in RDP patients. Atp1a3 was widely expressed in the brain, including basal ganglia and cerebellum, and spinal cord of young mice, and the expression pattern was compatible with movement abnormalities under lack of one of alleles. Our results demonstrated the usefulness of Atp1a3-deficient heterozygous mice as an animal model of RDP and its potential use to explore the pathophysiology of movement abnormality in this disorder.
authors.affiliation: Division of Biology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Division of Biology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan; Biology, Hyogo Medical College, Nishinomiya 663-8501, Hyogo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Division of Biology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan. Electronic address: kkawakam@jichi.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D020821:Dystonic Disorders / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006579:Heterozygote; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology*; D012149:Restraint, Physical; D012727:Sex Characteristics; D000254:Sodium-Potassium-Exchanging ATPase / Q000172:deficiency* / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology*
chemical_list: C526097:Atp1a3 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Chronic restraint stress; DYT12; Footprint analysis; Gene-knockout mice; Na,K-ATPase α3 subunit; Rapid-onset dystonia-parkinsonism (RDP)