BLOCKADE OF NMDA RECEPTORS INCREASES CELL-DEATH AND BIRTH IN THE DEVELOPING RAT DENTATE GYRUS

Excitatory input regulates cell birth and survival in many systems. Th e granule cell population of the rat dentate gyrus is formed primarily during the postnatal period. Excitatory afferents enter the dentate g yrus and begin to form synapses with granule cells during the first po stnatal week, the time of maximal cell birth and death. In order to de termine whether excitatory input plays a role in the regulation of cel l birth and survival in the developing granule cell layers and their g erminal regions, the subependymal layer and hilus, we treated rat pups with the N-methyl D-aspartate (NMDA) receptor antagonists MK-801, CGP 37849, or CGP 43487 during the first postnatal week and examined the numbers of H-3-thymidine-labeled cells, pyknotic cells, and healthy ce lls in these regions. In order to determine the cell type that was aff ected, sections from brains of MK-801-treated rats were processed for H-3-thymidine autoradiography combined with immunohistochemistry for t he marker of radial glia, vimentin, and the marker of mature astrocyte s, glial fibrillary acidic protein (GFAP).Within the dentate gyrus, NM DA receptor blockade resulted in the following changes: (1) the densit y of H-3-thymidine-labeled cells was increased, (2) the density of pyk notic cells was increased, (3) the density of 3H-thymidine-labeled pyk notic cells was increased, and (4) the density of healthy cells was de creased. The infrapyramidal blade/hilus showed changes throughout its extent, whereas the suprapyramidal blade showed changes only at the ro stral level. No change in the numbers of H-3-thymidine-labeled vimenti n-immunoreactive or GFAP-immunoreactive cells was observed in the dent ate gyrus with MK-801 treatment, indicating that glia are not primaril y affected by NMDA receptor blockade. Blockade of NMDA receptors resul ted in gross morphologic changes in the dentate gyrus; in most cases, the infrapyramidal blade was indistinguishable from the hilus. Moreove r, in several brains of animals treated with CGP 37849 or CGP 43487 on postnatal day (P)5, an abnormal aggregation of cells was observed ven tral to the normal location of the infrapyramidal blade. This cellular cluster contained many pyknotic and H-3-thymidine-labeled cells and m ay represent cells that normally comprise the infrapyramidal blade. Dr amatic changes to the subependymal layer were also seen following NMDA receptor blockade. The cross-sectional area of this region was signif icantly increased with MK-801, CGP 37849, or CGP 43487 treatment and c ontained a high density of H-3-thymidine-labeled cells and H-3-thymidi ne-labeled pyknotic cells. These results indicate that NMDA receptor a ctivation is critical for the normal development of the rat dentate gy rus. The finding that blockade of NMDA receptors resulted in increased levels of cell death and birth supports the hypothesis that NMDA rece ptor activation is a natural signal for the inhibition of these proces ses in the developing dentate gyrus. (C) 1994 Wiley-Liss, Inc.