Excitotoxicity in glial cells
Introduction
To understand how aberrant glutamate signaling can cause excitotoxicity, we will first summarize current knowledge of glutamate receptors and transporters and their expression in glial cells. Subsequently, we will provide a description of what is known about excitotoxicity in neurons and mention its putative relevance to neurodegenerative diseases of the central nervous system (CNS). Then, the evidence for excitotoxicity in glial cells will be discussed as well as the cell death mechanisms activated by over-activation of glutamate receptors. This information will finally be placed in the context of CNS diseases in which glial cell excitotoxicity may be a component of the etiology.
Section snippets
Glutamate signalling in the CNS
The main determinants of glutamate signaling are glutamate receptors and transporters. Glutamate activates ionotropic receptors, which gate membrane ion channels permeable to cations and metabotropic receptors, which are coupled to G proteins (for reviews, see Michaelis, 1998, Dingledine et al., 1999). Molecular cloning has revealed that each receptor subtype is composed of several subunits with high homology within each receptor class. Thus, functional AMPA receptors are formed by GluR1–4,
Glutamate receptors and transporters in glial cells
Functional glutamate receptors and transporters are expressed in gray as well as in white matter tracts (for recent reviews, see Matute et al., 1999, Verkhratsky and Steinhäuser, 2000, Danbolt, 2001).
Ionotropic glutamate receptors, mainly of the AMPA and kainate type, are expressed by astrocytes, oligodendrocytes (Table 1) and their precursors. Activation of these receptors on glial cells produces a large variety of biological responses, including the release of neurotransmitters and growth
Enhanced glutamate signals can lead to excitotoxic cell death
Excitotoxicity is a phenomenon whereby prolonged activation of excitatory amino acid receptors leads to cell death. It was first described in the late 1950s by Lucas and Newhouse (1957), who observed that sustained exposure to glutamate destroys retinal neurons. Later, Olney and Sharpe (1969) found that this vulnerability is shared by all central neurons bearing excitatory amino acid receptors, and they hypothesized later that glutamate receptor overactivation might be a primary cause of the
Excitotoxicity in glial cells: types involved
Many studies carried out over the last few years have shown that, in addition to neurons, glial cells can die by excitotoxicity. The main glial cell types vulnerable to excitotoxicity belong to the oligodendrocyte lineage. However, there is evidence that sustained activation of ionotropic glutamate receptors can also kill astrocytes and microglia.
Excitotoxicity and calcium homeostasis
Ionotropic glutamate receptors mediating excitotoxicity are permeable to Ca2+, a property that varies from one receptor subclass to another. High concentrations of extracellular glutamate generated, for instance, after traumatic and ischemic CNS injury result in overstimulation of AMPA, kainate and NMDA receptors and, as a consequence, in the influx of Na+ and Ca2+ ions through the pores formed by these receptors. Na+ influx can in turn trigger a secondary increase in the intracellular Ca2+
Ca2+ overflow and mitochondrial function
The types of excitotoxic cell death observed depend on the intensity and duration of exposure and involve two temporally distinct phases of necrosis and apoptosis, a feature that relies on mitochondrial physiology. Mitochondria accumulate much of the Ca2+ that enters the cell during excitotoxic insult, and blockade of this process prevents cell death Stout et al., 1998, Rego et al., 2001. Thus, it seems that mitochondrial Ca2+ accumulation is a critical event leading to the dysfunction of this
Hypoxia-ischemia related diseases
Excitotoxicity appears to be the predominant mechanism underlying ischemic damage (for a recent review, see Lee et al., 1999). Like neurons, differentiated oligodendrocytes in mixed glial cultures are very sensitive to transient oxygen and glucose deprivation. After 1 h under these conditions, the viability of oligodendrocytes is severely impaired, an effect that is attenuated by AMPA/kainate antagonists (McDonald et al., 1998). This indicates that glutamate released from astrocytes may
Conclusions
Like neurons, glial cells are sensitive to excitotoxicity. Among them, oligodendrocytes display great vulnerability to over-activation of AMPA and kainate receptors. Cell death is initiated by alterations in calcium homeostasis which, in turn, lead to mitochondrial damage. The vulnerability of oligodendrocytes to glutamate signals raises the possibility that excitotoxicity may be a component in the etiology of CNS demyelinating disorders. A thorough understanding of oligodendroglial
Acknowledgements
We are thankful to Marı́a Domercq for critical reading of the manuscript. The studies carried out in our laboratory were supported by Ministerio de Sanidad y Consumo, Gobierno Vasco, Universidad del Paı́s Vasco, Iberdrola y Fundación “La Caixa”. E. Alberdi is a research fellow of the Ramón y Cajal Program of the Ministerio de Ciencia y Tecnologı́a, and G. Ibarretxe holds a fellowship from Gobierno Vasco.
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