DEVELOPMENTAL-CHANGES IN ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONATE RECEPTOR PROPERTIES AND EXPRESSION IN THE RAT HIPPOCAMPAL-FORMATION

The developmental changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazol e propionate (AMPA) receptor properties in rat hippocampus were evalua ted with quantitative autoradiography of ligand binding and in situ hy bridization performed in adjacent sections with antisense oligonucleot ides for AMPA receptor subunits (GluR1-3, hip and flop splice variants ). Specific H-3-AMPA binding in different hippocampal subfields increa sed between postnatal day 7 and 15 and was higher in CA3 during the po stnatal period when compared to adult levels. This effect was mostly d ue to high levels of high affinity binding sites in cell body layers d uring the developmental period. By contrast, autoradiograms of H-3-AMP A binding predominantly to the low affinity binding sites indicated an absence of these sites in cell body layers and the overall levels of binding exhibited little overshoot compared to adult levels during the developmental period. The changes in binding of the antagonist of the AMPA receptor, 6-nitro-7-cyanoquinoxaline-2,3-dione were markedly dif ferent from those for the high affinity AMPA binding sites but quite s imilar to those for the low affinity sites. The binding was extremely low af postnatal day 7 and increased rapidly between postnatal day 7 a nd 15 and slowly between postnatal day 15 and adult. Low levels of bin ding were observed in the cell body layer at every postnatal age. The changes in expression of messenger RNAs for the different subunits of the AMPA receptors were well correlated with the modifications in high affinity AMPA binding sites measured in the cell body layers also exh ibiting an increased expression of the receptors at the transcriptiona l level during the developmental period as compared to adult levels. T he relative expression of the GluR2 subunits decreased during the post natal period and the time course for this reduction paralleled that fo r the increased vulnerability of hippocampal pyramidal neurons to a va riety of insults. The results indicate that both the messenger RNAs fo r the subunits and the AMPA receptors exhibit increased levels of expr ession during the postnatal period compared to adult levels. They also suggest that nascent receptors might bind AMPA with high affinity bef ore their insertion in membranes into functional receptors that have l ow affinity for agonists and high affinity for antagonists. The change s in subunit composition of the receptors during the postnatal period may have important implications for mechanisms of plasticity as well a s of neuropathology.