A ROLE FOR GLUTAMATE AND ITS RECEPTORS IN THE REGULATION OF OLIGODENDROCYTE DEVELOPMENT IN CEREBELLAR TISSUE-SLICES

We tested the hypothesis that the neurotransmitter glutamate would inf luence glial proliferation and differentiation in a cytoarchitecturall y intact system. Postnatal day 6 cerebellar slices were maintained in organotypic culture and treated with glutamate receptor agonists or an tagonists. After dissociation, cells were stained with antibodies for different oligodendrocyte developmentally regulated antigens, Treatmen t of the slices with the glutamate receptor agonists kainate or lpha-a mino-3-hydroxy-5-methyl-4-isoxazolepropionic acid significantly decrea sed the percentage of LB1(+), NG2(+) and O4(+) cells, and their bromod eoxyuridine labeling index. The non-N-methyl-D-aspartate glutamate rec eptor antagonist 6,7-dinitroquinoxaline-2,3-dione increased the percen tage and bromodeoxyuridine labeling of LB1(+), NG2(+) and O4(+) cells. In intact slices, RNA levels of the oligodendrocyte gene for 2',3'-cy dic nucleotide 3'-phosphodiesterase were decreased by kainate and lpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and increased by 6,7-dinitroquinoxaline-2,3-dione. The percentage of astrocytes was not modified by kainate, lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropion ic acid or 6,7-dinitroquinoxaline-2,3-dione, Treatment with the N-meth yl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid d id not alter the percentage of O4(+) cells, nor their proliferation. I ncubation with the gamma-aminobutyric acid receptor antagonist bicucul line did not modify the percentage of LB1(+), A2B5(+) and O4(+) cells. In purified cerebellar oligodendrocyte progenitor cells, glutamate re ceptor agonists blocked Kf currents, and inhibited cell proliferation and lineage progression. The K+ channel blocker tetraethylammonium als o inhibited oligodendrocyte progenitor cell proliferation. These findi ngs indicate that in rat cerebellar tissue slices: (i) glutamate speci fically modulates oligodendrocyte but not astrocyte development throug h selective activation of lpha-amino-3-hydroxy-5-methyl-4-isoxazolepro pionic acid receptors, and (ii) cell depolarization and blockage of vo ltage-dependent K+ channels is likely to be the triggering mechanism.