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The Journal of Neuroscience, March 22, 2006, 26(12):3220-3228; doi:10.1523/JNEUROSCI.3780-05.2006
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Cellular/Molecular
Activation of Kainate Receptors Sensitizes Oligodendrocytes to Complement Attack
Elena Alberdi, María Victoria Sánchez-Gómez, Iratxe Torre, María Domercq, Alberto Pérez-Samartín, Fernando Pérez-Cerdá, andCarlos Matute Departamento de Neurociencias, Universidad del País Vasco, E-48940 Leioa, Vizcaya, Spain
Correspondence should be addressed to Carlos Matute, Departamento de Neurociencias, Universidad del País Vasco, Barrio de Sarriena s/n, 48940 Leioa, Spain. Email: carlos.matute{at}ehu.es
Glutamate excitotoxicity and complement attack have both been implicated separately in the generation of tissue damage in multiple sclerosis and in its animal model, experimental autoimmune encephalomyelitis. Here, we investigated whether glutamate receptor activation sensitizes oligodendrocytes to complement attack. We found that a brief incubation with glutamate followed by exposure to complement was lethal to oligodendrocytes in vitro and in freshly isolated optic nerves. Complement toxicity was induced by activation of kainate but not of AMPA receptors and was abolished by removing calcium from the medium during glutamate priming. Dose–response studies showed that sensitization to complement attack is induced by two distinct kainate receptor populations displaying high and low affinities for glutamate. Oligodendrocyte death by complement required the formation of the membrane attack complex, which in turn increased membrane conductance and induced calcium overload and mitochondrial depolarization as well as a rise in the level of reactive oxygen species. Treatment with the antioxidant Trolox and inhibition of poly(ADP-ribose) polymerase-1, but not of caspases, protected oligodendrocytes against damage induced by complement. These findings indicate that glutamate sensitization of oligodendrocytes to complement attack may contribute to white matter damage in acute and chronic neurological disorders.
Key words: kainate receptors; glutamate; complement; calcium; oxidative stress; oligodendrocytes
Received Sept. 7, 2005; revised Feb. 9, 2006; accepted Feb. 9, 2006.
Correspondence should be addressed to Carlos Matute, Departamento de Neurociencias, Universidad del País Vasco, Barrio de Sarriena s/n, 48940 Leioa, Spain. Email: carlos.matute{at}ehu.es
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