Developmental changes in magnesium regulation of the N-methyl-D-aspartate receptor

The NMDA (N-methyl- scD-aspartate) receptor is involved in the maturation of the central nervous system. Developmental processes dependent on the NMDA receptor would be facilitated if the receptor were more easily activated early in postnatal life. We tested the hypothesis that the NMDA receptor is more easily activated in developing animals via a decreased ability of Mg{dollar}sp{lcub}2+{rcub}{dollar} to block the NMDA receptor channel. The pharmacology of NMDA receptor function was studied by two methods: (1) NMDA-evoked depolarizations recorded from a grease-gap preparation of CA1 hippocampal pyramidal cells and (2) binding of ({dollar}sp3{dollar}H) TCP to the activated NMDA receptor in isolated hippocampal membranes.; The potency of Mg{dollar}sp{lcub}2+{rcub}{dollar} to inhibit NMDA-evoked depolarizations of CA1 hippocampal pyramidal cells increased during development. AMPA-induced depolarizations did not change. Polyamines were tested for their ability to alter NMDA-induced depolarizations in the absence and presence of Mg{dollar}sp{lcub}2+{rcub}{dollar}. No developmental differences were observed in the effects of exogenously added polyamine agonists or antagonists, suggesting that changes in the levels of endogenous polyamines were not responsible for the observed change in Mg{dollar}sp{lcub}2+{rcub}{dollar} potency.; The initial rate of ({dollar}sp3{dollar}H) TCP binding reflects access of the radioligand to its binding site within the NMDA receptor channel. The rate is influenced by the state of the receptor and its membrane environment, but not by membrane potential, intracellular constituents or the presence of spare receptors. Mg{dollar}sp{lcub}2+{rcub}{dollar} increased the amount of ({dollar}sp3{dollar}H) TCP bound at non-equilibrium time points, reflecting an increase in the rate of ({dollar}sp3{dollar}H) TCP binding. The Mg{dollar}sp{lcub}2+{rcub}{dollar}-stimulated increase in the amount of ({dollar}sp3{dollar}H) TCP bound after short incubations was greater in preparations from adult animals. This result supports the proposal that the NMDA receptor and/or its membrane environment is altered in developing animals.; These data 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, and the sensitivity of CNS neurons to NMDA receptor-dependent excitotoxicity.