Novel Mouse Model to Study Cerebellar Dysfunction in Multiple Sclerosis

Objective: To create an experimental model of cerebellar dysfunction (CD) affecting multiple sclerosis (MS) patients by injecting MS patient cerebrospinal fluid (CSF) into the cisterna magnum (CM) of mice.

Background: Cerebellar dysfunction affects a subset (11-33%) of MS patients, is often clinically disabling and poorly responsive to both disease modifying and symptom specific therapies. The widely used animal model of MS, experimental allergic encephalitis (EAE) is not a suitable model to investigate cerebellar dysfunction. An appropriate experimental model of CD would possibly lead to a better understanding of the pathogenesis of this manifestation and establish a basis for effective therapeutic strategies.

Design/Methods: The CM of three groups of mice were injected using 10 UL of concentrated CSF taken from MS patients with CD, CSF from MS patients without CD, and with 10 UL of saline. Post-injection, mice in each group were evaluated for motor function coordination using a rotarod paradigm, hourly for 10 hours and also at 24 hours. In this ongoing experiment we have thus far tested CSF derived from 10 patients with MS (5 with CD and 5 without CD) and all experiments were done in triplicate.

Results: There was a significant difference in motor function coordination measured by rotarod performance at the 1 and 2-hour time points post-injection between mice injected with CSF from MS patients with CD and the other two groups as determined by a two-way ANOVA and a post-hoc Bonferroni test.

Conclusions: Our data suggests that CM injection into mice with CSF derived from MS patients with CD results in motor coordination difficulties. This is not observed in the control groups. Furthermore, our results suggest that the underlying mechanism is based an alteration of neurotransmission which we are currently investigating.