Immunohistochemical techniques were employed to examine the changes in immunolabeling of the N-methyl-D-aspartate (NMDA) receptor subunits NMDAR1 and NMDAR2A/B within the hippocampus 1, 3, 7, 14 and 30 days after a unilateral perforant pathway lesion was made in a rat brain. At 1 day post-lesion, we observed a decrease in NMDAR1 immunolabeling in the granule cells in the dentate gyrus as well as in the mossy cells in the polymorphic region ipsilateral to the lesion, while an increase in diffuse neuropil labeling was observed. At 3 days post-lesion, we observed a marked increase in NMDAR1 immunolabeling in the outer molecular-layer of the dentate gyrus as well as in the stratum moleculare in the CA fields ipsilateral to the lesion. Although this increase was less marked at 7 and 14 days post-lesion, an increase in NMDAR1 immunolabeling was evident at 30 days post-lesion. In contrast, although a transient increase in NMDAR2A/B immunolabeling was observed in the outer molecular layer at 3 days post-lesion, no other changes were detectable at any of the time points examined. Our study suggests that each subunit of the NMDA receptor displays a different response to deafferentation of the perforant pathway. We have previously observed that changes in the immunoreactivity of the receptor subunits of another class of glutamate receptor, a-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA), occur at 30 days post-lesion but not after a relatively short survival time. NMDA receptor subunits demonstrate an earlier response to the loss of the perforant pathway fibers than do the AMPA receptor subunits.