Patients with multiple sclerosis (MS) can develop cerebellar dysfunction (CD) with clinical manifestations ranging from mild abnormalities, such as tremor, to severe disabilities involving motor coordination and balance. Progress to understand CD in MS has been hampered by lack of animal models. We developed a rodent cisterna magna injection protocol, using cerebrospinal fluid (CSF) from MS patients with CD, that recapitulate the coordination deficits observed in these patients. Furthermore, since metabotropic glutamate receptors (mGluRs) have been suggested to have a functional relationship with cerebellar discoordination, we examined their impact on motor control disabilities.
To develop an animal model that replicates MS-specific cerebellar manifestations, and to investigate the role of mGluRs signaling pathway/s on cerebellar dysfunction in MS.
We injected into the mice cisterna magna 10 μl of concentrated (20X) CSF. Post-surgery, motor coordination performances of the mice were tested using the rotarod paradigm and their latency to fall from the drum rotating at 24 rpm was recorded. We analyzed 25 CSF samples from MS patients with or without CD. In a pharmacological approach, we examined the mGluRs involvement in CD manifestations in MS by co-injecting CSF samples from MS patients with CD with 3,5-dihydroxyphenylglycine (DHPG) or L(+)-2-amino-4-phosphonobutyric acid (LAP4), two mGluRs agonists.
Our results indicated that the motor coordination of mice injected with CSF from MS patients with CD was significantly impaired in the first four hours post-injection. By contrast, mice injected with CSF from MS patients without CD or mice injected with saline exhibited no abnormalities in their performances on the rotarod. Notably, co-injection experiments with mGluRs agonists DHPG and LAP4, significantly ameliorated the rotarod performances of mice injected with CSF from MS patients with CD.
We developed a novel animal model to study cerebellar dysfunction in MS. We observed that injection of CSF samples from MS patients with CD into the rodent cisterna magna gravely impaired their performance on the rotarod. Our pharmacological approach, using two agonists of mGluRs, suggests that cerebellar dysfunction in MS is the result of impairments in the activation and/or signaling of mGluRs pathways.