Neuroinflammation in the Normal-appearing White Matter (NAWM) of the Multiple Sclerosis Brain Causes Abnormalities at the Nodes of Ranvier

Overview

Journal PLoS Biol

Specialty Biology

Date 2020 Dec 14

PMID 33315860

Citations 18

Authors

Patricia Gallego-Delgado

Rachel James

Eleanor Browne

Joanna Meng

Swetha Umashankar

Li Tan

Carmen Picon

Nicholas D Mazarakis

A Aldo Faisal

Owain W Howell

Richard Reynolds

Affiliations

Soon will be listed here.

Abstract

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (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 N-methyl-D-aspartate (NMDA) receptor 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 pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits.

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