Glutamate is the principal excitatory neurotransmitter in the central nervous system (CNS), but it is also a potent neurotoxin that can kill nerve cells. Glutamate damages oligodendrocytes, like neurons, by excitotoxicity which is caused by sustained activation of AMPA, kainate and NMDA receptors. Glutamate excitotoxicity depends entirely on calcium overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death, which is prevented by glutamate receptor antagonists. In turn, activated, but not resting microglia, can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity, which is attenuated by AMPA/kainate antagonists or by the blockade of the system xc_ antiporter present in microglia. On the other hand, non-lethal, brief activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack. Intriguingly, these effects are exclusively mediated by kainate receptors which induce calcium overload of the cytosol and the generation of reactive oxygen species.
In addition, ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X7 purinergic receptors expressed by these cells. Sustained activation of P2X7 receptors in vivo causes lesions that are reminiscent of the major features of MSplaques, i.e., demyelination, oligodendrocyte death, and axonal damage. In addition, treatment with P2X7 antagonists of chronic experimental autoimmune encephalomyelitis (EAE), a model of MS, reduces demyelination and ameliorates the associated neurological symptoms. Together, these results indicate that ATP can kill oligodendrocytes via P2X7 activation and that this cell death process contributes to EAE. Importantly, P2X7 expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease. Thus, P2X7 receptor antagonists may be beneficial for the treatment of MS.
In conjunction, these observations reveal novel mechanisms by which altered glutamate and ATP homeostasis can trigger oligodendrocyte death. This knowledge may generate new therapeutic avenues to protect white matter from acute and chronic damage.
Supported by CIBERNED, Ministerio de Educación y Ciencia, Gobierno Vasco and Universidad del País Vasco.