Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier.

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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Gallego-Delgado P,James R,Browne E,Meng J,Umashankar S,Tan L,Picon C,Mazarakis ND,Faisal AA,Howell OW,Reynolds R

doi

10.1371/journal.pbio.3001008

subject

Has Abstract

pub_date

2020-12-14 00:00:00

pages

e3001008

issue

12

eissn

1544-9173

issn

1545-7885

pii

PBIOLOGY-D-20-01878

journal_volume

18

pub_type

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