Glutamate Induces c‐fos Proto‐oncogene Expression and Inhibits Proliferation in Oligodendrocyte Progenitors: Receptor Characterization

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Abstract
The effect of glutamate on c‐fos expression in oligodendrocyte progenitors was investigated by Northern blot analysis. Glutamate caused rapid and transient induction. Both 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione (CNQX) and 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX), two competitive non‐NMDA ionotropic receptor antagonists, reduced glutamate‐induced c‐fos expression, whereas the NMDA antagonist MK‐801 was ineffective. In addition, the glutamate receptor agonists (±)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid hydrobromide (AMPA) and kainate strongly induced c‐fos. However, the metabotropic receptor agonist trans‐(±)‐1‐amino‐(1S,3R)‐cyclopentanedicarboxylic acid (trans‐(±)‐ACPD) did not increase c‐fos mRNA level and the antagonist L‐(+)‐2‐amino‐3‐phosphonopropionic acid did not block glutamate‐induced c‐fos mRNA. These findings indicate that c‐fos induction in oligodendrocyte progenitors is mediated through the AMPA/kainate receptors, while NMDA and metabotropic receptor subtypes are not involved. Chelation of extracellular calcium by EDTA prevented glutamate‐induced c‐fos expression. Similarly, the protein kinase C inhibitor 1‐(5‐isoquinoline‐sulphonyl)‐2‐methylpiperazine dihydrochloride (H7) and down‐regulation of protein kinase C by prolonged exposure to phorbol‐12‐myristate 13‐acetate blocked c‐fos induction. These results suggest that induction of c‐fos through AMPA/kainate receptors is dependent on extracellular calcium influx and involves downstream activation of phorbol ester‐sensitive protein kinase C. The effect of glutamate on oligodendrocyte progenitor proliferation was assessed by [3H]thymidine incorporation. Glutamate and the agonists kainate and AMPA, but not trans‐(±)‐ACPD, caused a dose‐dependent decrease in [3H]thymidine incorporation. All these pharmacological agents were not toxic to oligodendrocyte progenitors. CNQX reversed the inhibitory effects produced by glutamate and the various agonists. These results suggest that glutamate may modulate the growth and differentiation of oligodendrocytes in the central nervous system.