Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination

Abstract

Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS). The precise role of microglia during demyelination, and the relative contributions of microglia vs. peripheral macrophages, are incompletely understood. Here, using a genetic fate mapping strategy, we identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Pharmacological depletion of microglia demonstrates these cells are necessary for the demyelination, loss of oligodendrocytes, and reactive astrocytosis normally evident in this model. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these damaged myelin sheaths are lost upon-repopulation of microglia. Injection of colony-stimulating factor-1 to drive focal microgliosis in white matter is sufficient to induce focal demyelination in vivo. These studies indicate activated microglia are required for demyelination that results from primary myelin pathology and are sufficient to induce demyelination directly.