Fig. 1.

Summary of the interplay of immune and neural mechanisms associated with NBAs in multiple sclerosis. A) Soluble factors released by microglia, astrocytes or immune cells (such as lymphocytes, not depicted) modulate synaptic neurotransmission, in this case mediated by glutamate, and induce myelin damage. These soluble factors can directly cause oligodendrocyte death, as well. Some therapeutic strategies operate by blocking the release of these factors. B) Alterations in synaptic transmission in MS explain NBAs. Glutamate-mediated excitotoxicity leads to neuronal death, which could be caused by TNFα through enhanced Ca²⁺ permeability in GluA2-deficient AMPA receptors or decreased glutamate uptake by EAAT1. Also, IFNγ and PGE2 induce indolamine-2,3-dioxygenase expression which results in serotonin deficiency and quinolinic synthesis, the latter causing NMDA receptor activation and excitotoxicity. On the contrary, kynurenic acid blocks NMDA receptors and might contribute to microglia-dependent synaptic pruning. Excessive intracellular Ca²⁺ disrupts mitochondrial buffering capacity and causes energy failure.