Astrocytes regulate N-methyl-D-aspartate receptor subunit composition increasing neuronal sensitivity to excitotoxicity

We have examined the dependence of rat cerebellar granule neurons (CGNs) fo r protection against glutamate toxicity. Under co-culture conditions, rat C GNs require astrocytes to protect against glutamate. The CGNs become more s ensitive to glutamate toxicity in co culture than when grown in cultures wi th only low numbers of astrocytes. If the protection of the astroyctes was withdrawn or blocked, this sensitivity led to neuronal death. Differing cha nges in NMDA receptor subunit subtype composition were noted depending on t he conditions in which the CGNs were grown. Suppression of individual NMDA subunit subtypes by oligonucleotide knockdown resulted in inhibition of tox icity. This result implies that astrocytes regulate the expression of NMDA receptor subunit subtypes which influence neuronal sensitivity to glutamate toxicity.