A PROTECTIVE ROLE PLAYED BY THE TRANSCRIPTIONAL REPRESSOR REST/NRSF IN A MOUSE MODEL OF MULTIPLE SCLEROSIS

Neuroinflammation causes neuronal dysfunctions that contribute to the pathogenesis of multiple sclerosis and of its mouse model, the experimental autoimmune encephalomyelitis (EAE). Neuroinflammation is also associated with the upregulation of the transcriptional repressor REST (RE1-silencing transcription factor), a master regulator of neuron-specific genes. Its contribution to promoting or protecting from the pathology remains to be clarified. Here, we found that REST is upregulated in neurons in the spinal cord during EAE in association with a consistent downregulation of REST-repressed genes. We knocked out REST in neurons of the lower central nervous system of mice, by injecting AAV vectors expressing CRE or its recombinase-defective variant (deltaCRE) intra cisterna magna at birth, and induced EAE after 8 weeks by immunization with the autoantigen myelin-oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). We observed that REST depletion is associated with an experience-dependent decrease in the latency-to-fall time on an accelerating Rotarod compared to deltaCRE-treated EAE mice, and with lower walking performance in the open field. Although the treatment did not significantly affect clinical score and weight changes in female EAE mice, in males it was associated with a higher peak score and trends towards a larger relative weight loss and a higher disease incidence. The treatment was not associated with differences in serum levels of major cytokines confirming purely neuronal mechanisms underlying the observed behavioural effects. Our data therefore show that, during EAE, REST is upregulated in neurons and indicate that this may protect from EAE-induced motor impairments through its role in gene regulation.