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Blockade of NMDA receptors increases cell death and birth in the developing rat dentate gyrus
E Gould1, H A Cameron, B S McEwen
1Laboratory of Neuroendocrinology, Rockefeller University, New York, New York 10021.
Insights
NMDA receptor antagonists disrupt normal cell development in the rat dentate gyrus, increasing cell death and altering cell birth during the critical first postnatal week. These findings highlight the role of excitatory input in regulating neurogenesis and survival.
Area of Science:
- Neuroscience
- Developmental Biology
- Neuropharmacology
Background:
- Excitatory input is crucial for regulating cell proliferation and survival in developing neural systems.
- The granule cell population of the rat dentate gyrus is primarily formed during the postnatal period, coinciding with synaptogenesis and high rates of cell birth and death.
Purpose of the Study:
- To investigate the role of excitatory input, specifically N-methyl D-aspartate (NMDA) receptor activity, in regulating cell birth and survival within the developing dentate gyrus and its germinal regions.
- To determine the impact of NMDA receptor antagonists on cell proliferation, cell death, and overall morphology of the developing dentate gyrus.
Main Methods:
- Postnatal rat pups were treated with NMDA receptor antagonists (MK-801, CGP 37849, CGP 43487) during the first postnatal week.
- Quantification of 3H-thymidine-labeled cells (proliferation), pyknotic cells (cell death), and healthy cells was performed in the dentate gyrus, subependymal layer, and hilus.
- Immunohistochemistry for vimentin and glial fibrillary acidic protein (GFAP) was used to assess glial cell involvement in MK-801 treated brains.
Main Results:
- NMDA receptor blockade increased the density of 3H-thymidine-labeled cells, pyknotic cells, and 3H-thymidine-labeled pyknotic cells, while decreasing healthy cell density in the dentate gyrus.
- Gross morphological alterations were observed, particularly in the infrapyramidal blade and hilus, with abnormal cell aggregations noted in some cases.
- Significant increases in the cross-sectional area of the subependymal layer were observed, containing high densities of proliferating and dying cells.
Conclusions:
- NMDA receptor blockade profoundly disrupts normal cell birth and survival in the developing rat dentate gyrus, leading to increased cell death and aberrant proliferation.
- The observed morphological changes and cell death suggest that excitatory input via NMDA receptors is essential for proper granule cell development and survival.
- NMDA receptor antagonists significantly impact the subependymal layer, indicating a role in regulating the germinal zone during early development.
Abstract:
Excitatory input regulates cell birth and survival in many systems. The granule cell population of the rat dentate gyrus is formed primarily during the postnatal period. Excitatory afferents enter the dentate gyrus and begin to form synapses with granule cells during the first postnatal week, the time of maximal cell birth and death. In order to determine whether excitatory input plays a role in the regulation of cell birth and survival in the developing granule cell layers and their germinal 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 3H-thymidine-labeled cells, pyknotic cells, and healthy cells in these regions. In order to determine the cell type that was affected, sections from brains of MK-801-treated rats were processed for 3H-thymidine autoradiography combined with immunohistochemistry for the marker of radial glia, vimentin, and the marker of mature astrocytes, glial fibrillary acidic protein (GFAP). Within the dentate gyrus, NMDA receptor blockade resulted in the following changes: (1) the density of 3H-thymidine-labeled cells was increased, (2) the density of pyknotic cells was increased, (3) the density of 3H-thymidine-labeled pyknotic cells was increased, and (4) the density of healthy cells was decreased. The infrapyramidal blade/hilus showed changes throughout its extent, whereas the suprapyramidal blade showed changes only at the rostral level. No change in the numbers of 3H-thymidine-labeled vimentin-immunoreactive or GFAP-immunoreactive cells was observed in the dentate gyrus with MK-801 treatment, indicating that glia are not primarily affected by NMDA receptor blockade. Blockade of NMDA receptors resulted in gross morphologic changes in the dentate gyrus; in most cases, the infrapyramidal blade was indistinguishable from the hilus. Moreover, in several brains of animals treated with CGP 37849 or CGP 43487 on postnatal day (P)5, an abnormal aggregation of cells was observed ventral to the normal location of the infrapyramidal blade. This cellular cluster contained many pyknotic and 3H-thymidine-labeled cells and may represent cells that normally comprise the infrapyramidal blade. Dramatic changes to the subependymal layer were also seen following NMDA receptor blockade. The cross-sectional area of this region was significantly increased with MK-801, CGP 37849, or CGP 43487 treatment and contained a high density of 3H-thymidine-labeled cells and 3H-thymidine-labeled pyknotic cells.(ABSTRACT TRUNCATED AT 400 WORDS)