To develop an animal model for cerebellar dysfunction (CD) in multiple sclerosis (MS) and investigate the role of metabotropic glutamate receptor (mGluR) signaling in CD. 

CD causes motor coordination deficits and affects up to one-third of patients with MS; however, there is currently no experimental model that replicates these clinical manifestations. mGluRs are implicated in motor discoordination, suggesting a molecular mechanism for CD. 

We designed a novel animal model for CD by injecting concentrated (20X) cerebrospinal fluid (CSF) from MS patients with or without CD (MS+CD, MS) or saline into the cisterna magna (CM) of mice. Motor coordination was assessed using the rotarod paradigm hourly for 8h and at 24h post-injection. Mice were also co-injected with CSF from MS+CD and 3,5-Dihydroxyphenylglycine (DHPG) or L(+)-2-amino-4-phosphonobutyric acid (LAP4), two mGluR agonists.

We also used a xenogeneic approach whereby primary rat neurons were cultured for 24h and treated with CSF from MS, MS+CD, or artificial CSF (aCSF). mGluR1 and mGluR5 synaptic protein and mRNA levels were evaluated.

We previously reported that CM injection of CSF from MS+CD caused impaired rotarod performance in mice compared to injection of CSF from MS or saline, but these effects were ameliorated by co-injection of DHPG or LAP4.

Our latest data indicated changes in synaptic mGluR protein levels. We also detected an increase of mGluR1 mRNA in neuronal cell cultures treated with CSF from MS+CD relative to treatment with CSF from MS or aCSF. The same effect was not observed in mGluR5.

Intracisternal injection of CSF from MS+CD is a novel animal model for the clinical manifestations of CD. Improvement in motor coordination with co-injection with DHPG and LAP4, as well as the changes in mGluR protein expression and increases in mGluR1 transcription, suggest that CD in MS is mediated by dysfunction of mGluR signaling pathways.