Glutamate‐mediated glial injury: Mechanisms and clinical importance

Abstract

Primary and/or secondary glial cell death can cause and/or aggravate human diseases of the central nervous system (CNS). Like neurons, glial cells are vulnerable to glutamate insults. Astrocytes, microglia, and oligodendrocytes express a wide variety of glutamate receptors and transporters that mediate many of the deleterious effects of glutamate. Astrocytes are responsible for most glutamate uptake in synaptic and nonsynaptic areas and consequently, are the major regulators of glutamate homeostasis. Microglia in turn may secrete cytokines, which can impair glutamate uptake and reduce the expression of glutamate transporters. Finally, oligodendrocytes, the myelinating cells of the CNS, are very sensitive to excessive glutamate signaling, which can lead to the apoptosis or necrosis of these cells. This review aims at summarizing the mechanisms leading to glial cell death as a consequence of alterations in glutamate signaling, and their clinical relevance. A thorough understanding of these events will undoubtedly lead to better therapeutic strategies to treat CNS diseases affecting glia and in particular, those that involve damage to white matter tracts.

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

“…Elevated glutamate levels can be detected in white matter after HI, 46,80,81 and as discussed previously, OPCs are sensitive to glutamate release and will die by apoptosis. The importance of glutamate toxicity in HI was demonstrated using a rat pup model of carotid ligation with hypoxia.…”

“…42 Interestingly, OL vulnerability to glutamate was first shown in culture by Oka et al 43 as mediated by GluTs, but it was later shown that GluRs also mediate OL excitotoxicity. 44,45 Excitotoxic cell death in OLs can be mediated in different ways (reviewed in Matute et al 46 ). In many cases, a calcium influx is generated by AMPA/kainate receptor activity.…”

“…102,103 Cytokines released by activated microglia have been shown to trigger OL apoptosis (reviewed in Aktas et al 104 ) and microglia can also trigger excitotoxicity-induced apoptosis in OPCs by releasing glutamate. 46,105,106 Autoantibodies against epitopes within myelin and related proteins have been commonly observed in MS. 107 However, some autoantibodies seem to recognize epitopes, such as NG2, that are expressed only in OPCs. 108 Similarly, a heat shock protein (HSP) expressed selectively in OPCs is another autoantibody target in MS. 109 In vitro studies with this anti-HSP autoantibody determined that complement-mediated death occurred in OPCs, but not in pro-OLs.…”

Glia: the fulcrum of brain diseases

“…17 Immature and adult oligodendrocytes are 68 This feature is relevant to stroke as well as to preterm and perinatal ischaemia. Thus, in vivo models of stroke and cardiac arrest such as permanent middle cerebral artery occlusion and brief transient global ischaemia induce rapid oligodendroglial death.…”

“…Damage to oligodendrocytes triggers Wallerian degeneration and invariably results in axonal demise. 17 Finally, the microglia, which populates the whole of the brain parenchyma and dwells in relatively independent territorial domains, is the only system of specific immune and cellular defence, residing beyond the blood-brain barrier. 18 Malfunction of glia therefore is fatal for the nervous system; all in all glial cells can survive and operate in the presence of dead or dying neurones; neurones, however, cannot survive in the absence of glia.…”