Trends in Neurosciences
Volume 24, Issue 4, 1 April 2001, Pages 224-230
Journal home page for Trends in Neurosciences

Review
The link between excitotoxic oligodendroglial death and demyelinating diseases

https://doi.org/10.1016/S0166-2236(00)01746-XGet rights and content

Abstract

Oligodendrocytes, the myelinating cells of CNS axons, are highly vulnerable to excitotoxic signals mediated by glutamate receptors of the AMPA and kainate classes. Receptors in these cells are commonly activated by glutamate that is released from axons and glial cells. In addition, oligodendrocytes contribute to the control of extracellular glutamate levels by means of their own transporters. However, acute and chronic alterations in glutamate homeostasis can result in overactivation of AMPA and kainate receptors and subsequent excitotoxic oligodendroglial death. Furthermore, demyelinating lesions caused by excitotoxins can be similar to those observed in multiple sclerosis. This, together with the effect of AMPA and kainate receptor antagonists in ameliorating the neurological score of animals with experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis), indicates that oligodendrocyte excitotoxicity could be involved in the pathogenesis of demyelinating disorders.

Section snippets

All major types of CNS glial cells participate in glutamate signaling

Glutamate activates ionotropic and metabotropic receptors present in neurons and glial cells. Ionotropic GluRs can directly mediate excitotoxicity.18 According to pharmacological, electrophysiological and molecular properties, ionotropic GluRs are classified as AMPA (subunits GluR1–4), kainate (subunits GluR5–7 and KA1–2) and NMDA (subunits NR1 and NR2A–D) receptors.18, 19, 20 However, it should be noted that in spite of this nomenclature, kainate activates both AMPA and kainate receptors.21

Overactivation of glutamate receptors is toxic to oligodendrocytes

GluR-mediated toxicity has been observed in an oligodendroglial cell line10 and in differentiated oligodendrocytes in vitro.11, 12 This toxicity is triggered by overactivation of AMPA and kainate receptors11, 12, 29 and, similar to neurons, it is directly related to Ca2+ influx subsequent to receptor activation11, 12, 29 (Box 1). The fact that these experiments were made in pure cultures of oligodendrocytes indicates that excitotoxicity is caused by direct activation of oligodendroglial

Relevance of oligodendroglial excitotoxicity to demyelinating disorders of the CNS

The observations described above indicate that overactivation of AMPA and kainate receptors causes injury to oligodendrocytes both in vitro and in vivo, and that this toxicity is relevant to acute insults such as ischemia. Is this oligodendroglial death mechanism also involved in the pathogenesis of demyelinating diseases of the CNS? These disorders comprise those central white matter diseases with a suspected or confirmed autoimmune basis.16 Among these, the most devastating is multiple

Concluding remarks

Over the past few years, the concept of excitotoxic damage to oligodendrocytes has been established using several experimental models. Excitotoxic oligodendroglial death occurs in white matter ischemic lesions and in EAE, the most widely accepted animal model of MS. The findings described herein could open novel avenues for the development of new drugs to treat demyelinating disorders. It remains to clarify the cellular and molecular events leading to alterations in glutamate homeostasis and

Acknowledgements

The authors’ research is funded by the Ministerio de Educación y Cultura, Gobierno Vasco, Universidad del Paı́s Vasco and by Iberdrola. We thank F. Conti, A. Verkhratsky, A. Volterra and D.J. Fogarty for critical reading of the manuscript.

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      WM supports the development of the majority of oligodendrocytes that facilitate NMDA (glutamate) receptor expression, essential for excitatory postsynaptic currents while preventing WM excitotoxic damage (Matute, 2011). Therefore, it has been suggested that glutamate excitotoxicity can lead to neuronal death and axon demyelination (Dias, 2012; Kim et al., 2010; Matute et al., 2001; Pitt et al., 2000). To the best of our knowledge, only a few studies have investigated the link between abnormal glutamate levels and WM damage in neuropsychiatric disorders (Bustillo et al., 2017; León-Ortiz et al., 2020; Poletti et al., 2019a; Reid et al., 2016).

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