Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation

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 xc− 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.

Effect of modulating glutamate signaling on myelinating oligodendrocytes and their development—A study in the zebrafish model

“…One of our major findings in the zebrafish model is that signaling mechanisms regulating myelination are dependent on the extracellular glutamate concentration. In support of this finding are a number of reports showing that myelination can be controlled by regulating vesicular release from neurons reporting from cell culture (Wake et al, 2011(Wake et al, , 2015, mouse (Evonuk et al, 2020;Kougioumtzidou et al, 2017), and other zebrafish models (Hines et al, 2015;Koudelka et al, 2016;Mensch et al, 2015). In the latter report, the authors evaluated myelin sheet dynamics along single axons over time using live imaging approaches within the zf model and proposed a general role for vesicular-possibly glutamaterelease in the elongation of maturing myelin sheets.…”

Transient Receptor Potential Melastatin 3 Is Functionally Expressed in Oligodendrocyte Precursor Cells and Is Upregulated in Ischemic Demyelinated Lesions

“…While AMPA receptors in OPCs are physiologically important for oligodendrocyte survival, 7) excessive Ca 2+ influx via AMPA receptors in oligodendrocytes exacerbates demyelination in multiple sclerosis model. 45) In the ischemia experiment (Fig. 4), enhanced TRPM3 expression in OPCs may disrupt intracellular Ca 2+ homeostasis, leading to dysfunction of the cells.…”

Novel Toolboxes for the Investigation of Activity-Dependent Myelination in the Central Nervous System

“…OPCs gradually lose synaptic contacts with neurons during their differentiation into oligodendrocytes, accompanied by a downregulation of ionotropic glutamate receptors (De Biase et al, 2010 ; Kukley et al, 2010 ). Nevertheless, Evonuk et al ( 2020 ) crossed the PLP-CreER line with Gria 4tm1Mony mice (Fuchs et al, 2007 ) to specifically knock-out GluA4 in more mature PLP + oligodendroglial cells. They reported that deleting GluA4 ameliorated myelin degeneration and axonal damage in a mouse model of multiple sclerosis (Evonuk et al, 2020 ).…”

“…Nevertheless, Evonuk et al ( 2020 ) crossed the PLP-CreER line with Gria 4tm1Mony mice (Fuchs et al, 2007 ) to specifically knock-out GluA4 in more mature PLP + oligodendroglial cells. They reported that deleting GluA4 ameliorated myelin degeneration and axonal damage in a mouse model of multiple sclerosis (Evonuk et al, 2020 ). Oligodendrocyte lineage cells also express NMDA receptors (Káradóttir et al, 2005 , 2008 ; Salter and Fern, 2005 ; Micu et al, 2006 ).…”