The protective effect of Fingolimod upon visual behavior in a demyelination animal model is associated with synaptopathy prevention

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that causes motor, cognitive, and sensory dysfunctions, with visual disorder being one of the most prevalent. Synaptopathy has been recognized as one of the predominant pathogenic components of MS. We previous characterized inhibition of synaptopathy in the visual thalamus using the cuprizone-induced demyelination MS animal model. However, investigations about potential treatments to prevent synaptopathy have received little attention. Fingolimod is one of the most widely used and effective immunomodulators for controlling inflammatory relapses in MS, but few studies in MS animal models have tested its effect on synaptopathy. Given that none of these investigations used the cuprizone-induced demyelination model, our study investigated the preventive effect of Fingolimod on cuprizone-induced synaptopathy. Using Western blotting for synaptophysin, PSD-95, and gephyrin, as well as ultrastructural analysis, we demonstrated that daily intraperitoneal injections of Fingolimod (1 mg/Kg) protect against the increase of inhibitory synapses in cuprizone-treated mice. Fingolimod also prevented reduction of ARC immunolabeling, a sensor of neuronal activity, in cuprizone animals. Finally, through the visual Cliff test, Fingolimod was able to protect cuprizone animals against visual dysfunction. On the other hand, through immunostaining for CNPase, GFAP and IBA-1 we observed that Fingolimod failed to prevent demyelination and glial reactivity in the cuprizone animals. Taken together, the data indicate the potential of preventive treatment with Fingolimod against synaptopathy and visual dysfunction associated with inflammatory demyelination.