FGF2 and FGFR1 signaling regulate functional recovery following cuprizone demyelination

Abstract

In demyelinating diseases, such as multiple sclerosis, remyelination offers the potential to recover function of viable denuded axons by restoring saltatory conduction and/or protecting from further damage. Mice with genetic reduction of fibroblast growth factor 2 (Fgf2) or Fgf receptor 1 (Fgfr1) exhibit dramatically improved remyelination following experimental demyelination with cuprizone. The current studies are the first to test neurobehavioral outcomes with these gene deletions that improved remyelination. The cuprizone protocols used did not produce overt abnormalities but did reduce bilateral sensorimotor coordination (complex wheel task) and increase sociability (two chamber apparatus with novel mouse). A significant effect of genotype was observed on the complex wheel task but not in the sociability apparatus. Specifically, complex wheel velocities for Fgf2 nulls improved significantly after removal of cuprizone from the diet. This improvement in Fgf2 null mice occurred following either acute (6 wk) or chronic (12 wk) demyelination. Plp/CreERT:Fgfr1fl/fl mice administered tamoxifen at 10 wks of cuprizone treatment to induce Fgfr1 knockdown also showed improved recovery of running velocities on the complex wheels. Therefore, constitutive deletion of Fgf2 or Fgfr1 knockdown in oligodendrocyte lineage cells is sufficient to overcome impairment of sensorimotor coordination after cuprizone demyelination.

Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior

“…This plateau velocity has been shown to significantly decrease in conditions with extensive demyelination of the corpus callosum. 41,42 The single-impact model with more-extensive corpus callosum pathology also did not alter the running on the complex wheel (Supplementary Fig. 6A) (see online supplementary material at ).…”

“…Training wheels were then replaced with “complex” wheels, which have irregularly spaced rungs. 41,42 Mice were run in two independent cohorts that each had 6 mice assigned to each condition. The total assay included 24 mice, with 12 injured and 12 matched sham mice.…”

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

“…In fact, bFGF delivered into cerebrospinal fluid disrupts developmental myelination in neonates, causing OPC accumulation and eventually demyelination in the adult (Butt and Dinsdale, 2005a, b; Goddard et al, 2001). bFGF inhibits remyelination through FGFR1, as its genetic ablation in OPCs improves the generation of OLs as well as sensorimotor coordination in a chronic cuprizone demyelination model (Mierzwa et al, 2013; Zhou et al, 2012). Some of the pathological effects of high bFGF levels may be mediated by astrocytes and microglia, as raising bFGF in ventricular cerebrospinal fluid of neonatal rats led to astroglial and microglial reactivity (Goddard et al, 2002).…”

Leukemia/lymphoma‐related factor (LRF) exhibits stage‐ and context‐dependent transcriptional controls in the oligodendrocyte lineage and modulates remyelination

“…Longitudinal analysis of behavior was included in the study design to assess the behavioral effect of LRF knockdown during the subsequent remyelination period (Figure S4). Running activity on wheels with a complex pattern of rungs was used to detect impaired maximal running velocity, which is associated with myelination status of the corpus callosum in longitudinal studies of mice fed cuprizone (Hibbits, Pannu, Wu, & Armstrong, ; Mierzwa, Zhou, Hibbits, Vana, & Armstrong, ). In the current study, mice had wheels continuously available for running and every third week the wheel was changed from a training wheel (all rungs in place) to a complex wheel (non‐uniform pattern of missing rungs).…”