GLUTAMATE REGULATES INTRACELLULAR CALCIUM AND GENE-EXPRESSION IN OLIGODENDROCYTE PROGENITORS THROUGH THE ACTIVATION OF LPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTORS

Oligodendrocytes and their progenitors (O-2A) express functional kaina te- and lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) -preferring glutamate receptors. The physiological consequences of act ivation of these receptors were studied in purified rat cortical O-2A progenitors and in the primary oligodendrocyte cell line CG-4. Changes in the mRNA levels of a set of immediate early genes were studied and were correlated to intracellular Ca2+ concentration, as measured by f ura-2 Ca2+ imaging. Both in CG-4 and in cortical O-2A progenitors, bas al mRNA levels of NGFI-A were much higher than c-fos, c-jun, or jun-b. Glutamate, kainate, and AMPA greatly increased NGFI-A mRNA and protei n by activation of membrane receptors in a Ca2+-dependent fashion. Ago nists at non-N-methyl-D-aspartate receptors promoted transmembrane Ca2 + influx through voltage-dependent channels as well as kainate and/or AMPA channels. The influx of Ca2+ ions occurring through glutamate-gat ed channels was sufficient by itself to increase the expression of NGF I-A mRNA. AMPA receptors were found to be directly involved in intrace llular Ca2+ and NGFI-A mRNA regulation, because the effects of kainate were greatly enhanced by cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA but not kainate recepto rs. Our results indicate that glutamate acting at AMPA receptors regul ates immediate early gene expression in cells of the oligodendrocyte l ineage by increasing intracellular calcium. Consequently, modulation o f these receptor channels may have immediate effects at the genomic le vel and regulate oligodendrocyte development at critical stages.