Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.
Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.
Department of Neurology, University of California, San Francisco, San Francisco, United States.|Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China.
Feng
F
Mei
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Klaus
K
Lehmann-Horn
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Yun-An A
YA
Shen
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Kelsey A
KA
Rankin
Inception Sciences, San Diego, United States.
Karin J
KJ
Stebbins
Inception Sciences, San Diego, United States.
Daniel S
DS
Lorrain
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Kara
K
Pekarek
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Sharon
S
A Sagan
Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China.
Lan
L
Xiao
Department of Medicine, Immunobiology Program, University of Vermont, Burlington, United States.
Cory
C
Teuscher
Department of Neurology, University of California, San Francisco, San Francisco, United States.
H-Christian
HC
von Büdingen
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.
Jürgen
J
Wess
Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, United States.
J Josh
JJ
Lawrence
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Ari J
AJ
Green
Department of Neurology, University of California, San Francisco, San Francisco, United States.|Department of Pediatrics, University of California, San Francisco, San Francisco, United States.
Stephen Pj
SP
Fancy
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Scott S
SS
Zamvil
Department of Neurology, University of California, San Francisco, San Francisco, United States.
Jonah R
http://orcid.org/0000-0002-2176-1242
JR
Chan
demyelination; mouse; myelination; neuroscience; oligodendrocytes; rat
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