title: Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 ΔGAG heterozygous knock-in mice.
abstract: DYT1 dystonia is a movement disorder caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), corresponding to a glutamic acid loss in the C-terminal region of torsinA. Functional alterations in the basal ganglia circuits have been reported in both DYT1 dystonia patients and rodent models. Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits and decreased striatal dopamine receptor 2 (D2R) binding activity, suggesting a malfunction of the indirect pathway. However, the role of the direct pathway in pathogenesis of dystonia is not yet clear. Here, we report that Dyt1 KI mice exhibit significantly decreased striatal dopamine receptor 1 (D1R) binding activity and D1R protein levels, suggesting the alteration of the direct pathway. The decreased D1R may be caused by translational or post-translational processes since Dyt1 KI mice had normal levels of striatal D1R mRNA and a normal number of striatal neurons expressing D1R. Levels of striatal ionotropic glutamate receptor subunits, dopamine transporter, acetylcholine muscarinic M4 receptor and adenosine A2A receptor were not altered suggesting a specificity of affected polytopic membrane-associated proteins. Contribution of the direct pathway to motor-skill learning has been suggested in another pharmacological rat model injected with a D1R antagonist. In the present study, we developed a novel motor skill transfer test for mice and found deficits in Dyt1 KI mice. Further characterization of both the direct and the indirect pathways in Dyt1 KI mice will aid the development of novel therapeutic drugs.
authors.affiliation: Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610-0236, USA.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokoi
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Mai T
authors.initials: MT
authors.lastname: Dang
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610-0236, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gandre
authors.affiliation: Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610-0236, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kwon
authors.affiliation: Department of Radiology, School of Medicine, Saint Louis University, Saint Louis, MO 63104, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Yuen
authors.affiliation: Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610-0236, USA. Electronic address: yuqing.li@neurology.ufl.edu.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D007858:Learning / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics*; D009043:Motor Activity / Q000235:genetics*; D009048:Motor Skills / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: C491548:Dyt1 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2
keywords: DYT1; Direct pathway; Dopamine receptor; Dystonia; Motor-skill transfer; TorsinA