Oligodendrocyte N-Methyl-d-aspartate Receptor Signaling: Insights into Its Functions

Abstract

Myelination by oligodendrocytes facilitates rapid nerve conduction. Loss of oligodendrocytes and failure of myelination lead to nerve degeneration and numerous demyelinating white matter diseases. N-methyl-D-aspartate (NMDA) receptors, which are key regulators on neuron survival and functions, have been recently identified to express in oligodendrocytes, especially in the myelin sheath. NMDA receptor signaling in oligodendrocytes plays crucial roles in energy metabolism and myelination. In the present review, we highlight the subcellular location-specific impairment of excessive NMDA receptor signaling on oligodendrocyte energy metabolism in soma and myelin, and the mechanisms including Ca(2+) overload, acidotoxicity, mitochondria dysfunction, and impairment of respiratory chains. Conversely, physiological NMDA receptor signaling regulates differentiation and migration of oligodendrocytes. How can we use above knowledge to treat excitotoxic oligodendrocyte loss, congenital myelination deficiency, or postnatal demyelination? A thorough understanding of NMDA receptor signaling-mediated cellular events in oligodendrocytes at the pathophysiological level will no doubt aid in exploring effective therapeutic strategies for demyelinating white matter diseases.

Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?

“…NMDARs are indeed expressed in immature and mature oligodendrocytes. Activation of these receptors in oligodendrocytes modulates their metabolism, promotes their differentiation from immature into mature stage, and favors myelination around axons (Cao and Yao, 2013; Li et al, 2013). Interestingly, NMDAR activation promotes the differentiation of cultured oligodendrocytes via NOX-mediated ROS (Cavaliere et al, 2012).…”

Neuroglial Transmission

“…Glutamate function is therefore an obvious therapeutic target in diseases involving white matter (57,256). However, white matter is home to glia-glia and glia-neuronal interactions mediated by most of the transmitters operating in grey matter, including glutamatergic, purinergic, GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic, and serotonergic signaling (recent review in Ref.…”

D‐Aspartate treatment attenuates myelin damage and stimulates myelin repair

“…Consistent with the OPC maturation promoting effects of D‐Asp through a mechanism involving the activation of both AMPA and NMDA receptors, it has been shown that glutamate signaling regulates both the initiation and completion of oligodendrocyte differentiation through the concerted activation of both these ionotropic glutamate receptors. In fact, whereas the activation of AMPA receptors regulates the early phase of OPC proliferation and initial differentiation, NMDA receptor activity regulates the morphological aspects of oligodendrocytes and the transition of immature to mature oligodendrocyte stage (Wake et al , ; Cavaliere et al , ; Cao & Yao, ; Li et al , ; Lundgaard et al , ; Martinez‐Lozada et al , ). Remarkably, the pivotal role played by these receptors in orchestrating OPC development is highlighted by recent studies showing that AMPA receptor signaling in oligodendrocyte lineage cells promotes OPC maturation and postnatal myelination by stimulating survival of newly differentiating oligodendrocytes (Kougioumtzidou et al , ), and blocking AMPA/kainate or NMDA receptors activity significantly inhibits remyelination (Li et al , ; Lundgaard et al , ; Gautier et al , ).…”

“…Wake et al, 2011;Cavaliere et al, 2012;Cao & Yao, 2013;Li et al, 2013;Lundgaard et al, 2013;Martinez-Lozada et al, 2014). Remarkably, the pivotal role played by these receptors in orchestrating OPC development is highlighted Effects of D-Aspartate treatment on corpus callosum remyelination.…”