No abstract

Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the CNS characterized by both grey and white matter injury. Microglial activation and a reduction in synaptic density are key features of grey matter pathology that can be modeled with experimental autoimmune encephalomyelitis (EAE). Complement deposition combined with microglial engulfment has been shown during normal development and in disease as a mechanism for pruning synapses. We tested whether there is excess complement production in the EAE hippocampus and whether complement-dependent synapse loss is a source of degeneration in EAE using C1qa and C3 knockout mice. We found that C1q and C3 protein levels were elevated in EAE mice. Genetic loss of C1qa provided a small degree of protection from EAE-induced decreases in synaptic density. However, C1qa knockout EAE mice had similar levels of microglial activation and identical clinical scores as WT EAE mice. C3 knockout mice were largely protected from EAE-induced synapse loss and microglial activation, results that correlated with a reduction in the EAE clinical score. Thus, pathologic expression and activation of the early complement pathway drives a portion of the synapse elimination observed in the EAE grey matter.