Multiple sclerosis (MS), an autoimmune disorder of the central nervous system (CNS), is characterized by inflammatory cell infiltration and myelin destruction. In addition to systemic activation of peripheral immune cells, the activation and proliferation of astrocytes and microglia observed in demyelinated lesions suggest that the innate immune response by CNS resident cells may also contribute to MS pathogenesis. While recent evidence suggests that voltage- gated Ca2+ channels (VGCCs)—specifically the L-type Cav1.2 subunit—are centrally involved in triggering astrocyte reactivity, it is unknown how they influence demyelinating diseases precipitated by autoimmunity. Thus, utilizing an animal model of MS called experimental autoimmune encephalomyelitis (EAE), we sought to determine whether voltage-gated Ca2+ entry in astrocytes promotes astrocyte reactivity, neuroinflammation, and demyelination. We disrupted normal Cav1.2 functioning in astrocytes via deletion by Cre-lox recombination and inhibition by the L-type calcium channel antagonist nimodipine. We observed trends for accentuated disease severity and motor impairment in mice treated with nimodipine during the acute phase of EAE and when astrocytic Cav1.2 was ablated prior to EAE induction. However, we also observed a trend for attenuated disease severity and greater motor activity in mice treated with nimodipine during peak EAE symptomology. Although reactive astrogliosis was seemingly unaffected by Cav1.2 deletion or inhibition, we did observe significant reductions in microglia activation and lymphocyte infiltration, as well as myelin protection, indicating reduced cytotoxic factor release by reactive astrocytes in the brain and spinal cord of our Cav1.2KO and nimodipine-treated mice. These findings suggest that Ca2+ entry via Cav1.2 in astrocytes augments neuroinflammation and demyelination, as well as the functionality of reactive astrocytes, during autoimmunity. These data also reveal that a reactive astrocytic response during the peak of autoimmunity is detrimental to recovery, however further evidence is required to elucidate any significant phenotypic differences. Our data may facilitate the discovery of novel drug therapies, or repurposing of other dihydropyridines, that preferentially target Cav1.2 channels and ameliorate the pathophysiology of demyelinating diseases induced by autoimmunity.
What will the audience learn from your presentation?
- Hopefully, my research will impress upon researchers the importance of targeting astrocytic Cav1.2 channels to ameliorate symptoms in autoimmune diseases.
- This may inspire others to investigate how dihydropyridines may affect multiple sclerosis.
- Also, this work may provide a foundation upon which researchers can develop novel pharmaceutical therapeutics for multiple sclerosis.