Effects of commissural de- and remyelination on motor skill behaviour in the cuprizone mouse model of multiple sclerosis.

Feeding of copper chelator cuprizone induces reversible demyelination, predominantly of the corpus callosum in C57/Bl6 mice. With the availability of knockout and transgenic mice, this animal model of multiple sclerosis has increasingly attracted scientists to study the roles of various factors involved in de- and remyelination. However, central motor deficits have not been reported in this model so far. In the present study, we introduce a novel murine motor test, the motor skill sequence (MOSS). This test is designed to detect latent deficits in motor performance. In a first step, we habituated mice to training wheels composed of regularly spaced crossbars till maximal wheel-running performance was achieved. Subsequently, the animals were exposed to wheels with irregularly spaced crossbars demanding high-level motor coordination. This two-step approach minimized a contribution of cardiopulmonary and musculoskeletal training to any improvement of motor performance on the complex wheels. We applied the MOSS test under acute cuprizone-induced demyelination as well as in remyelinated mice after cuprizone withdrawal. Demyelinated animals on a cuprizone diet already showed reduced running performance on the training wheels as compared to control animals. This was even more pronounced when these mice were subsequently exposed to the complex wheels. In contrast, remyelinated animals after cuprizone withdrawal did not exhibit any functional impairment on the training wheels. Latent motor skill deficits were however revealed on the complex wheels, although clearly ameliorated as compared to acutely demyelinated mice. Our results show that latent motor deficits of cuprizone-induced demyelination and after remyelination can be quantified by MOSS. This motor test thus expands the usability of the cuprizone model to a functional level and might also be applicable to other animal models of human CNS diseases associated with subtle motor deficits of central origin.