Journal article
Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation
Science advances, Vol.6(2), pp.eaax5936-eaax5936
01/01/2020
DOI: 10.1126/sciadv.aax5936
PMCID: PMC6949032
PMID: 31934627
Abstract
Glutamate dysregulation occurs in multiple sclerosis (MS), but whether excitotoxic mechanisms in mature oligodendrocytes contribute to demyelination and axonal injury is unexplored. Although current treatments modulate the immune system, long-term disability ensues, highlighting the need for neuroprotection. Glutamate is elevated before T2-visible white matter lesions appear in MS. We previously reported that myelin-reactive T cells provoke microglia to release glutamate from the system x(c)(-) transporter promoting myelin degradation in experimental autoimmune encephalomyelitis (EAE). Here, we explore the target for glutamate in mature oligodendrocytes. Most glutamate-stimulated calcium influx into oligodendrocyte somas is AMPA receptor (AMPAR)-mediated, and genetic deletion of AMPAR subunit GluA4 decreased intracellular calcium responses. Inducible deletion of GluA4 on mature oligodendrocytes attenuated EAE and loss of myelinated axons was selectively reduced compared to unmyelinated axons. These data link AMPAR signaling in mature oligodendrocytes to the pathophysiology of myelinated axons, demonstrating glutamate regulation as a potential neuroprotective strategy in MS.
Details
- Title: Subtitle
- Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation
- Creators
- Kirsten S. Evonuk - Cleveland ClinicRyan E. Doyle - Cleveland ClinicCarson E. Moseley - University of Alabama at BirminghamIan M. Thornell - University of Alabama at BirminghamKeith Adler - Cleveland ClinicAmanda M. Bingaman - Cleveland ClinicMark O. Bevensee - University of Alabama at BirminghamCasey T. Weaver - University of Alabama at BirminghamBooki Min - Cleveland ClinicTara M. DeSilva - Cleveland Clinic
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.6(2), pp.eaax5936-eaax5936
- Publisher
- Amer Assoc Advancement Science
- DOI
- 10.1126/sciadv.aax5936
- PMID
- 31934627
- PMCID
- PMC6949032
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Number of pages
- 13
- Grant note
- Mike L. Jezdimir Transverse Myelitis Foundation T32 AI007051-39 / National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) RO1EY025687; T32 EY024236-02 / National Eye Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI) P30-NS069324 / National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) FG-1807-31882 / National Multiple Sclerosis Society Postdoctoral Fellowship; National Multiple Sclerosis Society RG 4587-A-1 / National Multiple Sclerosis Society 1648822 / NSF; National Science Foundation (NSF)
- Language
- English
- Date published
- 01/01/2020
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984359939102771
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