Developing oligodendrocytes (OLs) are highly vulnerable to glutamate excitotoxicity. Although OL excitotoxicity is mainly mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors (AMPARs) and is Ca2+-dependent, the molecular basis for AMPAR-mediated Ca2+ influx in OLs remains largely unclear. Ca2+ permeability of AMPARs is inversely correlated with the abundance of the AMPAR subunit glutamate receptor 2 (GluR2). Here we report that GluR2-containing and GluR2-lacking AMPARs are co-expressed in individual OLs and that a subset of AMPARs on each OL are Ca2+-permeable and mediate OL excitotoxicity. Virus-mediated overexpression of GluR2 reduces OL excitotoxicity, whereas expression of its unedited form GluR2(Q) enhances the excitotoxicity. These findings indicate that GluR2 critically controls OL excitotoxicity. During OL excitotoxicity, the transcriptional factor cAMP-response element-binding protein (CREB) is transiently phosphorylated and subsequently down-regulated. Virus-mediated expression of a constitutively active form of CREB, both in cultured OLs in vitro and in developing cerebral white matter in vivo, up-regulates GluR2, inhibits Ca2+ permeability, and protects OLs from excitotoxicity. Overall, these data suggest that targeting GluR2-lacking AMPARs or CREB may be a useful strategy for treating nervous system disorders associated with OL excitotoxicity.