To characterize the role of oligodendroglial FGFR1 on cerebellar demyelination and axonal degeneration in MOG_35-55 induced EAE.

The cerebellum and its efferent and afferent pathways are affected in multiple sclerosis (MS). Recent studies on human brain tissue have shown that fibroblast growth factors (1, 2, 9) and its receptors (1 and 2) are involved in the pathogenesis of MS. We have shown that in MOG_35-55-induced EAE, the animal model of MS, Fgfr1^ind-/- mice show a less severe disease course, less demyelination and axonal degeneration in the spinal cord, an area predominantly affected in EAE. We hypothesized that oligodendroglial Fgfr1 also plays a role in the cerebellum in chronic EAE.

Tamoxifen induced deletion of Fgfr1 in oligodendrocytes was done in four-week-old female mice (referred to as Fgfr1^ind-/-). MOG_35-55-EAE was induced in eight to twelve-week-old Fgfr1^ind-/- mice. Tissue samples were collected on 62 p.i. Myelin loss, axonal degeneration, immune cell infiltration (T cells, B cells, macrophages) was analyzed by immunohistochemistry. ERK/AKT expression was measured by western blot.

Fgfr1^ind-/- mice showed a delayed onset of disease and milder disease course than control mice in the chronic phase of EAE (P ≤ 0.05).  In the cerebellum myelin loss was less in Fgfr1^ind-/- mice (P ≤ 0.05), axonal density and myelin expression was increased in Fgfr1^ind-/- mice (P ≤ 0.05) compared to controls. The number of B cells, T cells and macrophages was less in Fgfr1^ind-/- mice (P ≤ 0.05) compared to controls. Increased phosphorylation of ERK and AKT (P ≤ 0.05) was observed in Fgfr1^ind-/- mice compared to controls.

In the cerebellum, knockout of oligodendroglial Fgfr1 causes milder EAE symptoms, less axonal damage and less inflammation. These data suggest that phosphorylation of ERK/AKT in the cerebellum is the underlying mechanism that protects against demyelination and axonal degeneration in oligodendroglial FGFR1 conditional k.o. mice.