DEVELOPMENTAL INCREASE IN THE SENSITIVITY TO MAGNESIUM OF NMDA RECEPTORS ON CA1 HIPPOCAMPAL PYRAMIDAL CELLS

The N-methyl-d-aspartate (NMDA) receptor is involved in processes, such as associative learning, that are particularly important during early postnatal development. It has been suggested that the activity and regulation of this receptor changes during development. Activation of the NMDA receptor is normally limited by Mg2+ present in the extracellular fluid of brain. We have found that Mg2+ less potently antagonizes the depolarizing action of NMDA in developing rats than in adults. A grease-gap method was used to record depolarizations evoked in CA1 hippocampal pyramidal cells by the excitants NMDA and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate). In the adult CA1 area, Mg2+ shifted the NMDA concentration-response curve to the right in a manner consistent with voltage-dependent open channel block (uncompetitive antagonism) in a preparation with significant receptor reserve. The potency of Mg2+ increased during development; a greater than two-fold change in the EC50 for Mg2+ was observed between 10-15 days of age and adulthood. A concentration of 10 mM reduced the maximum response of CA1 pyramidal cells to NMDA in adult rats, but not in developing rats. In addition, Mg2+ often enhanced the maximum depolarizations evoked by NMDA in 10- to 15-day-old rats, but very seldom in adults. No significant developmental changes in AMPA-induced depolarizations were observed in the presence or absence of Mg2+. These results suggest that synaptically released glutamate will readily activate NMDA receptors during early development and that its ability to do this declines with the maturation of the brain. This may at least partially explain developmental reductions in learning ability, the ability to generate long-term potentiation, the ability to evoke kindling and the sensitivity of CNS neurons to NMDA receptor-dependent excitotoxicity. © 1990.