Microglial aggregation and demyelinating cortical pathology in mouse

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS) in young adults, with an autoimmune etiology. Currently approved therapies for MS are most effective at inflammatory stages of disease. The goal of our research is to establish an animal model for progressive MS (PMS). Subpial cortical lesions and grey matter pathology with minimal blood-brain barrier disruption are hallmarks of PMS, which are not well modelled by current animal models. Our aim is to create meningeal inflammation, with cortical inflammation with activated microglia/macrophages, in order to understand the role of microglia in the chronic lesion and the underlying pathological mechanisms.
We induced cortical inflammation by feeding the myelin toxin cuprizone to mice. Preliminary data showed small aggregates of activated Iba-1+ microglia with accompanying demyelination in cortical grey matter. These aggregates were intensified by subarachnoidal injection of cytokines and by intrathecal injections of lipopolysaccharide or neurodegeneration-primed microglia. We are optimizing an alternative approach of laser irradiation with skull thinning, that induces a similar focal subpial aggregate of activated microglia. The volume of the irradiation-induced lesion reduced by 5 days post-irradiation. However, prior intrathecal administration of a viral vector expressing interferon-gamma led to sustained microglial activation at 5 days post-irradiation. Flow cytometry showed increased numbers of CD11c+ microglia, as well as monocytes and myeloid cells, at 5 days compared to the contralateral unirradiated hemisphere.
We will further optimize and establish these novel animal models that mimic the hallmark pathology of PMS and investigate the underlying pathological mechanism and kinetics. This will improve our understanding of, and lead to better treatment of PMS.