title: Motor deficits and hyperactivity in cerebral cortex-specific Dyt1 conditional knockout mice.
abstract: DYT1 dystonia is a primary generalized early-onset torsion dystonia caused by mutations in DYT1 that codes for torsinA and has an autosomal dominant inheritance pattern with approximately 30% penetrance. Abnormal activity in the pallidal-thalamic-cortical circuit, especially in the globus pallidus internus, is the proposed cause of dystonic symptoms. However, recent neuroimaging studies suggest significant contribution of the cerebral cortex. To understand the contribution of the cerebral cortex to dystonia, we produced cerebral cortex-specific Dyt1 conditional knockout mice and analysed their behaviour. The conditional knockout mice exhibited motor deficits and hyperactivity that mimic the reported behavioural deficits in Dyt1 DeltaGAG knockin heterozygous and Dyt1 knockdown mice. Although the latter two mice exhibit lower levels of dopamine metabolites in the striatum, the conditional knockout mice did not show significant alterations in the striatal dopamine and its metabolites levels. The conditional knockout mice had well-developed whisker-related patterns in somatosensory cortex, suggesting formations of synapses and neural circuits were largely unaffected. The results suggest that the loss of torsinA function in the cerebral cortex alone is sufficient to induce behavioural deficits associated with Dyt1 DeltaGAG knockin mutation. Developing drugs targeting the cerebral cortex may produce novel medical treatments for DYT1 dystonia patients.
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: Fumiaki
authors.initials: F
authors.lastname: Yokoi
authors.forename: Mai Tu
authors.initials: MT
authors.lastname: Dang
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mitsui
authors.forename: Jianyong
authors.initials: J
authors.lastname: Li
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D004422:Dystonia Musculorum Deformans / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D018390:Gene Targeting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity; D017072:Neostriatum / Q000378:metabolism; D013003:Somatosensory Cortex / Q000473:pathology
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; D004298:Dopamine