UC San Diego

In this study, I characterize peripheral neuropathic phenotypes in F35 mice (knock-out model of prion disease) and 93N mice (novel knock-in model of prion disease) using various behavioral assays, electrophysiology, and histology. F35 mice and 93N mice show significant impairment of small unmyelinated C-fibers without systemic loss of nerve density in either the foot skins or the cornea. In analyzing large fiber function, F35 mice and 93N mice show significant slowing of motor nerve conduction velocity. However, only 93N male mice show significant impairment in large sensory nerve fiber function, suggesting a model- and sex-specific peripheral neuropathic phenotype in the knock-in model. Structural analysis of axon caliber distribution in sciatic nerves show significantly smaller mean axonal diameter in diseased mice, but no difference in total amount of large myelinated fibers. Overall, axonal size-frequency in sciatic nerves of diseased mice appear heavily skewed toward smaller nerve fibers. Analysis of myelin sheath g-ratio show thinner axon diameters in only F35 mice compared to wild type mice, but post-hoc analysis of only male mice shows that F35 and 93N males both have smaller axonal diameters compared to wild types. The presence of peripheral nerve pathology in both mice despite a lack of prion aggregates in the central nervous systems of both mouse models suggests that prion aggregates may not be necessary to activate prion neurotoxic pathways.