Amaral, 1991). This strict laminar organization allows for putative changes in GluR distribution at the laminar level to be interpreted at the level of intraneuronal compartmentalization (i.e., distal versus proximal dendrites) and with reference to an isolated excitatory circuit (i.e., the perforant path).

This quantitative analysis demonstrated that aged monkeys, compared with young adult monkeys, exhibit a decrease in the fluorescence intensity for the subunit NR1 in the outer molecular layer of the dentate gyrus compared with the inner molecular layer. Given the tight laminar organization of these circuits, this suggests that the decreased NR1 levels impact the input from the entorhinal cortex, but not the other excitatory inputs to the dentate gyrus, again, pointing to the entorhinal input to the hippocampus as a key element in age-related changes. Since NR1 is the obligatory subunit for the NMDA receptor, this shift probably represents a general shift in NMDA receptor localization. Parallel qualitative and quantitative studies with antibodies to AMPA and kainate subunits demonstrated that the intradendritic alteration in NRI occurs without a similar alteration of non-NMDA receptor subunits, even though all three classes of GluRs are colocalized within these dendrites (Siegel et al., 1995). Further analyses, using markers for presynaptic terminals and dendritic markers, demonstrated that these elements were structurally intact in these aged animals.

These findings suggested that, in aged monkeys, a circuit-specific alteration in the intradendritic concentration of NR1 occurs without concomitant gross structural changes in dendritic morphology or a significant change in the total synaptic density across the molecular layer, suggesting that the intradendritic distribution of a neurotransmitter receptor is modifiable in an age-related and circuit-specific manner. Such a shift would lead to compromised NMDA receptor-mediated transmission, which could explain age-related shifts in long-term potentiation and spatial memory (Barnes et al., 1997a, 1997b) in the absence of any purely structural damage.

While these results are compelling, in that they represent a particularly high level of both molecular and anatomic specificity for age-related shifts in circuit attributes, they also are limited in two important ways. First, the animals were not behaviorally characterized, so these neurobiological changes cannot be directly linked to functional change. Second, the aged animals were all females, and their endocrine status was not carefully monitored, although they were presumably all postmenopausal. Given that estrogen is known to affect circuit characteristics in the hippocampus (McEwen and Alves, 1999), perhaps the endocrine status of the aged animals contributed to the receptor changes as much or more than chronological age. Presently, the data are not available from aged primates to clarify this potential confound, but we investigated the cellular mechanisms of estrogen-induced NMDA receptor regulation at the protein and mRNA levels in ovariectomized (OVX) rats with and without estrogen replacement therapy (ERT), using immunocytochemical and

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