Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes

Abstract

In cultured oligodendrocytes isolated from perinatal rat optic nerves, we have analyzed the expression of ionotropic glutamate receptor subunits as well as the effect of the activation of these receptors on oligodendrocyte viability. Reverse transcription-PCR, in combination with immunocytochemistry, demonstrated that most oligodendrocytes differentiated in vitro express the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR3 and GluR4 and the kainate receptor subunits GluR6, GluR7, KA1 and KA2. Acute and chronic exposure to kainate caused extensive oligodendrocyte death in culture. This effect was partially prevented by the AMPA receptor antagonist GYKI 52466 and was completely abolished by the non-N-methyl-Daspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), suggesting that both AMPA and kainate receptors mediate the observed kainate toxicity. Furthermore, chronic application of kainate to optic nerves in vivo resulted in massive oligodendrocyte death which, as in vitro, could be prevented by coinfusion of the toxin with CNQX. These findings suggest that excessive activation of the ionotropic glutamate receptors expressed by oligodendrocytes may act as a negative regulator of the size of this cell population.The main function of oligodendrocytes is to myelinate axons in the vertebrate central nervous system. This cell type develops mostly soon after the majority of neurons are generated and have extended their axons and, therefore, it is likely that neurons play an important role in regulating oligodendrocyte development. In the rat optic nerve, the first fully differentiated oligodendrocytes appear after birth, and the definitive mature population of oligodendrocytes is reached around 6 weeks later (1, 2). The proliferation and the survival of oligodendrocytes depend, respectively, on the electrical activity of neighboring axons and in the reciprocal contacts they establish (for a recent review, see ref.3). Axon to oligodendrocyte signaling results in the generation of the precise number of oligodendrocytes necessary to myelinate entirely a given population of axons. Unfortunately, little information is available about the molecules participating in this signaling process.Oligodendrocytes express neurotransmitter receptors including those activated by glutamate (4). This excitatory amino acid acts at various types of receptors, which can be grouped into two major categories: ionotropic receptors, which gate membrane ion channels permeable to cations; and metabotropic receptors, which are coupled to G proteins. Ionotropic receptors are classified into ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-Daspartate (NMDA) subtypes, according to their preferred agonist. Molecular cloning has revealed that each receptor subtype is composed of several subunits with high homology within each receptor class (reviewed in ref. 5). Thus, AMPA receptors are formed by GluR1-4, kainate receptors by GluR5-7 and KA1-2, and NMDA rece...

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