To develop an experimental animal model for cerebellar dysfunction (CD) in multiple sclerosis (MS) in order to identify potential molecular pathways relevant to CD.

Cerebellar dysfunction, which causes impaired motor coordination, affects up to one-third of patients with MS. The cause is not well understood since the current experimental model of MS does not adequately replicate the clinical manifestations of CD. Although the pathways involved are currently unknown, recent studies have implicated group 1 metabotropic glutamate receptors (mGluRs) in motor coordination deficits, suggesting a potential molecular mechanism involved in CD.

We designed a novel CD model by injecting concentrated (20X, 10µl) cerebrospinal fluid (CSF) from MS patients into the cisterna magna (CM) of mice. Mice received injections of either CSF from MS patients with CD, CSF from MS patients without CD, or saline. Motor coordination was evaluated using a rotarod test hourly for 8 hours post-injection, and again at 24 hours.

We also administered -3,5-Dihydroxyphenylglycine (DHPG, 250mM), a selective agonist of group 1 mGluRs, co-injected with CSF from MS patients with CD, and compared this treatment against CSF from MS patients with CD co-injected with saline. The rotarod paradigm was used to evaluate motor coordination.

Mice injected with CSF from MS patients with CD showed significantly impaired rotarod performance compared to mice of the other two experimental groups, confirming that the CM injection technique can serve as a model for CD.

Co-injection of DHPG significantly ameliorated this motor deficit, indicating involvement of group 1 mGluRs in motor coordination disability in CD.

The data indicate that the CM injection of CSF from MS patients with CD can be used to model the clinical manifestations of CD. Performance improvement after co-injection of DHPG implicates group 1 mGluRs as potential targets for the mechanism of CD.