NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury

Abstract

Injury to oligodendrocyte processes, the structures responsible for myelination, is implicated in many forms of brain disorder. Here we show NMDA (N-methyl-D-aspartate) receptor subunit expression on oligodendrocyte processes, and the presence of NMDA receptor subunit messenger RNA in isolated white matter. NR1, NR2A, NR2B, NR2C, NR2D and NR3A subunits showed clustered expression in cell processes, but NR3B was absent. During modelled ischaemia, NMDA receptor activation resulted in rapid Ca2+-dependent detachment and disintegration of oligodendroglial processes in the white matter of mice expressing green fluorescent protein (GFP) specifically in oligodendrocytes (CNP-GFP mice). This effect occurred at mouse ages corresponding to both the initiation and the conclusion of myelination. NR1 subunits were found mainly in oligodendrocyte processes, whereas AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor subunits were mainly found in the somata. Consistent with this observation, injury to the somata was prevented by blocking AMPA/kainate receptors, and preventing injury to oligodendroglial processes required the blocking of NMDA receptors. The presence of NMDA receptors in oligodendrocyte processes explains why previous studies that have focused on the somata have not detected a role for NMDA receptors in oligodendrocyte injury. These NMDA receptors bestow a high sensitivity to acute injury and represent an important new target for drug development in a variety of brain disorders.

Functional glutamate transport in rodent optic nerve axons and glia

“…Expression of AMPA/kainate receptors is particularly marked in immature cells of the oligodendrocyte lineage (Itoh et al, 2002), which in the neonatal optic nerve are in the process of forming an exquisitely close morphological arrangement with neighbouring axons (Butt and Ransom, 1993). We and others have recently demonstrated the presence of functional NMDA-type glutamate receptors in oligodendrocyte processes (Salter and Fern, 2005;Káradóttir et al, 2005;Micu et al, 2006)). The activation of these receptors is likely to be important in a variety of diseases and must have significant developmental consequences.…”

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

“…Although, there are evidences for the expression of NMDA receptors on oligodendrocyte processes in white matter [19], oligodendrocytes in retro-orbital optic nerve axons remained normal. But astrocytes underwent reactive changes with the development of extensive filament-rich processes.…”

“…Studies have confirmed perisynaptic localisation of N-methyl-D-aspartate (NMDA) receptors in RGCs [17]. Although there is evidence for the presence of non-NMDA glutaminergic receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainite in the postsynaptic myelinated axons in the central neurons [18] and the expression of NMDA receptors on oligodendrocyte processes in white matter [19], there is no direct evidence of presence of functional NMDA receptors on axons [20]. Therefore, retro-orbital optic nerve axonal degeneration observed in NMDA-induced retinal insult is logically a consequence of primary damage to RGCs; however, damage to intraorbital axons can also be considered a primary site of insult, if future studies provide direct evidence for the presence of functional NMDA receptors over axons.…”

White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

“…Oligodendrocytes, expressing AMPA/kainate and N-methyl-D-aspartatereceptors, are also sensitive to glutamate toxicity, which is associated with caspase-3 activation, DNA fragmentation, apoptotic cell death, and demyelination (Domercq et al, 2005;Karadottir and Attwell, 2007;Salter and Fern, 2005;Xu et al, 2008). Damage of the myelin sheath itself may contribute to axonal degeneration by reducing trophic support to axons and impairing axonal transport (Nave, 2010).…”