ONTOGENY OF GLYCINE-ENHANCED (H-3)MK-801 BINDING TO N-METHYL-D-ASPARTATE RECEPTOR-COUPLED ION CHANNELS

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is thought to play a critical role in neuronal development, differentiation and plasticity, A number of studies have shown an enhanced sensitivity to NMDA receptor ligands in neonatal animals. This study examined the ontogenetic changes in the glycinergic modulation of NMDA-coupled cation channels in the developing central nervous system of rat pups. The nonequilibrium binding of the specific channel ligand [H-3]MK-801 was used as a measure of NMDA channel access. Glycine (10(-5) M) enhancement of [H-3]MK-801 binding at 2 h in forebrain membranes from adult rats was significantly greater than that observed in tissues from 8- to 28-day-old rat pups. This difference was due to changes in the efficacy, but not potency of glycine. The observed ontogenetic changes in the efficacy of glycine-enhanced [H-3]MK-801 binding were attributable to developmental changes in receptor site density, as determined by equilibrium [H-3]MK-801 saturation isotherms. Kinetic studies revealed that glycine increased the association rate constants of [H-3]K-801 in 8-day and adult membranes by a similar magnitude (0.111 +/- 0.021 vs 0.094 +/- 0.009 nM-1 h-1, respectively). Similarly, the fractional amount of[H-3]MK-801 bound (i.e., amount bound at time t normalized to amount bound at equilibrium) in the presence of glycine was relatively constant throughout neonatal development. These findings suggest that the allosteric modulation of the NMDA ionophore by glycine is similar in postnatal and adult rats. Hence, the reported developmental hypersensitivity of neonatal rats to NMDA ligands is probably not attributable to ontogenetic changes in the glycinergic modulation of the NMDA supramolecular complex.