Trends in Neurosciences
ReviewThe link between excitotoxic oligodendroglial death and demyelinating diseases
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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