Microglial depletion exacerbates axonal damage and motor dysfunction in mice with cuprizone-induced demyelination.

Abstract

The cuprizone (CPZ)-induced demyelination model, an animal model of Multiple sclerosis (MS), is characterized by demyelination and motor dysfunction due to microglial-mediated neuroinflammation. To determine the contribution of microglia to motor function during CPZ-induced demyelination, the microglia of mice in the CPZ-model were depleted using PLX3397 (PLX), an orally bioavailable selective colony stimulating factor 1 receptor inhibitor. PLX treatment aggravated motor dysfunction as shown by the pole, beam walk, ladder walk, and rotarod tests. PLX treatment removed microglia from the superior cerebellar peduncle (SCP), but not from the corpus callosum (CC). Although PLX treatment did not affect the degree of demyelination in both of CC and SCP, the expression of axonal damage marker APP (amyloid precursor protein) was increased. Increased TNF-α, IL-1β, and iNOS expressions were observed in PLX-treated mice. These results suggest that microglial depletion exacerbates axonal damage and motor dysfunction in CPZ model mice. In this study, we found that microglia contribute to motor function and axon-protective effects in CPZ-induced demyelination.