Neuroinflammation in the normal appearing white matter of multiple sclerosis brain causes abnormalities at the node of Ranvier

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of MS brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an NMDA blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by proinflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits.