A new mouse model of inflammatory cortical demyelination

Cortical damage is prominent in multiple sclerosis (MS) and associated with disease progression and cognitive impairment. Although subpial cortical demyelination is more specific for MS than demyelination of the white matter, little is known about the pathogenic requirements for inflammatory cortical demyelination. This study combines transgenic mice on a C57BL/6 background with a stereotactic targeting approach to characterize the immunological mechanisms of inflammatory cortical demyelination. Cortical demyelination as assessed by immunohistochemistry against myelin basic protein (MBP), was most pronounced at day 5 after lesion induction and paralleled by a significant reduction of p25+ adult and Olig2+ precursor oligodendrocytes. Time course experiments demonstrated the rapid resolution of cortical demyelination and a significant decrease of perivascular intracortical demyelination was already observable at day 20 after lesion induction. The number of APP+ axons was significantly higher around perivascularly demyelinated vessels, while the density of cortical neurons was not reduced. The inflammatory cortical infiltrate was composed of inflammatory monocytes, T cells, polymorphonuclear cells (PMNs) and natural killer (NK) cells. We depleted each cell population genetically or by antibody mediated cell depletion to assess their relevance for inflammatory cortical demyelination. A pathogenic antibody response and inflammatory monocytes were required for subpial cortical demyelination. Perivascular cortical demyelination was required in addition to encephalitogenic T cells and was augmented by NK cells. Adoptive transfer studies in RAG mice demonstrated that the antigen presenting functions of B cells were dispensable. In summary, we developed and characterized a novel inflammatory cortical demyelination model.