Linking synaptopathy and gray matter damage in multiple sclerosis.

Introduction Diffuse microglial and astroglial reactions indicate that the innate immune system is chronically activated in the gray matter of multiple sclerosis (MS) and of experimental autoimmune encephalomyelitis (EAE). How neuronal survival is influenced by reactive microglia and astroglia, whose activation should be protective or restorative in neurological diseases, is unclear. Based on recent observations in EAE and in MS studies, here we propose a mechanism of neuronal damage triggered by uncontrolled synaptic activation and excitotoxicity secondary to glial release of proinflammatory molecules able to regulate the sensitivity of glutamate receptors in neurons.