Journal of Biochemistry Advance Access published online on October 23, 2007
Journal of Biochemistry, doi:10.1093/jb/mvm191
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© 2007 The Japanese Biochemical Society
Motor deficits and hyperactivity in cerebral cortex-specific Dyt1 conditional knockout mice
1Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA; 2Medical Scholars Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA; 3Department of Neurobiology and Anatomy, Kochi Medical School, Oko-cho, Nankoku 783-8505, Japan; 4Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
*To whom correspondence should be addressed: Yuqing Li, 560 CIRC, 1530 3rd Avenue South, Birmingham, Alabama 35294-0017 USA. Tel.: 205-996-6299, Fax: 205-996-7200. E-mail: yli{at}uab.edu
Received September 7, 2007; Accepted September 30, 2007
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Abstract |
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SUMMARY
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 an 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 analyzed their behavior. The conditional knockout mice exhibited motor deficits and hyperactivity that mimic the reported behavioral deficits in Dyt1 
GAG 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 behavioral deficits associated with Dyt1 GAG knockin mutation. Developing drugs targeting the cerebral cortex may produce novel medical treatments for DYT1 dystonia patients.
Key Words: cerebral cortex, conditional knockout mouse, DYT1 dystonia, early-onset dystonia, torsinA
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