AB - Developing oligodendrocytes (OLs) are highly vulnerable to glutamate excitotoxicity. Although OL excitotoxicity is mainly mediated by α-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. Ca 2+ 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.
Withdrawal from chronic treatment with benzodiazepines is associated with increased neuronal excitability leading to anxiety, aversive effects and increased seizure sensitivity. After repeated withdrawal experiences, seizure sensitivity increases while withdrawal‐induced anxiety and aversion decrease. We used autoradiographical methods employing (3H)Ro48 8587, a selective ligand for glutamatergic α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA) receptors, to study withdrawal‐induced changes in AMPA receptor binding in areas of the mouse brain postulated to be involved in these responses. Mice were given 21 days treatment with diazepam (15 mg/kg, . in sesame oil) followed by withdrawal (single withdrawal) or three blocks of 7 days treatment interspersed with 3‐day periods to allow washout of drug (repeated withdrawal). In keeping with heightened excitability in withdrawal from chronic diazepam treatment, the single withdrawal group showed, 72 h after their final dose of diazepam, increased (3H)Ro48 8587 binding in several brain areas associated with emotional responses or seizure activity, including hippocampal subfields, amygdalar and thalamic nuclei and motor cortex. In contrast, the repeated withdrawal group showed no changes in (3H)Ro48 8587 binding in any brain area studied. These observations are consistent with up‐regulation of AMPA receptor‐mediated transmission being important in withdrawal‐induced anxiety and aversion but not in increased seizure sensitivity associated with repeated withdrawal. As changes in AMPA receptor subunit expression alter the functionality of the receptor, future studies will address this possibility.