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The Journal of Neuroscience, June 1, 2005, 25(22):5351-5355; doi:10.1523/JNEUROSCI.0855-05.2005

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Impaired Motor Learning in Mice Expressing TorsinA with the DYT1 Dystonia Mutation

Nutan Sharma,¹ Mark G. Baxter,² Jeremy Petravicz,¹ D. Cristopher Bragg,¹ Alonna Schienda,¹ David G. Standaert,¹ and Xandra O. Breakefield¹

¹Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and ²Department of Experimental Psychology, Oxford University, Oxford OX1 3UD, United Kingdom

Primary early-onset generalized dystonia is an autosomal dominant disorder caused by a deletion (GAG) in the DYT1 gene encoding torsinA. The gene defect has incomplete penetrance, with 30% of carriers developing clinically evident dystonia. We describe lines of transgenic mice that express either human mutant torsinA (hMT) or human wild-type (hWT) torsinA. All mice demonstrated moderately increased levels of torsinA in the brain by Western blot analysis and normal subcellular distribution of torsinA in neurons by confocal microscopy. No animals had dystonic features. However, mice overexpressing hMT, but not hWT, torsinA displayed a reduced ability to learn motor skills in an accelerating rotarod paradigm. This pattern resembles the impaired motor sequence learning demonstrated in human nonmanifesting carriers of the GAG mutation. Open-field testing showed no differences in spontaneous activity between transgenic mice and their nontransgenic littermates, indicating that mice overexpressing hMT torsinA did not develop overtly abnormal motor behavior. Together, these data suggest that these transgenic mice provide a useful model of the GAG carrier state that can be used to probe genetic and environmental factors that can trigger the dystonic state.

Key words: DYT1; transgenic mouse; motor learning; dystonia; TorsinA; nuclear envelope

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Received Dec 11, 2004; revised April 5, 2005; accepted April 10, 2005.

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