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 Bioljournal_title
PLoS biologyauthors
Gallego-Delgado P,James R,Browne E,Meng J,Umashankar S,Tan L,Picon C,Mazarakis ND,Faisal AA,Howell OW,Reynolds Rdoi
10.1371/journal.pbio.3001008subject
Has Abstractpub_date
2020-12-14 00:00:00pages
e3001008issue
12eissn
1544-9173issn
1545-7885pii
PBIOLOGY-D-20-01878journal_volume
18pub_type
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