Journal of Biochemistry Advance Access originally published online on October 23, 2007
Journal of Biochemistry 2008 143(1):39-47; 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, AL 35294; 2Medical Scholars Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; 3Department of Neurobiology and Anatomy, Kochi Medical School, Oko-cho, Nankoku 783-8505, Japan; and 4Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
*To whom correspondence should be addressed. Tel: +1-205-996-6299, Fax: +1-205-996-7200, E-mail: yli{at}uab.edu
Received September 7, 2007; Accepted September 30, 2007
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Abstract |
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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 
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 
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 behavioural 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
Abbreviations: DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; DYT1 (TOR1A), TorsinA gene in human; Dyt1 (Tor1a), TorsinA gene in mouse; HVA, homovanillic acid (3-methoxy-4-hydroxyphenylacetic acid); KO mouse, knockout mouse