promised glutamate release rather than degeneration of pre-or postsynaptic elements.
Most importantly, all three of the regions displaying decreased levels of SYN receive a major projection from layer II of entorhinal cortex, offering further evidence that this circuit is exquisitely sensitive to aging. These findings suggest that circuit-specific alterations in glutamate release in the hippocampus may contribute to the effects of aging on learning and memory, in the absence of frank degeneration. This is a compelling example of the power of using quantitative, chemically specific approaches in behaviorally characterized animals in order to pinpoint the subtle circuit-specific neurobiological substrates of age-related memory impairment.
In these same animals, we investigated the AMPA receptor subunit, GluR2, and the NMDA receptor subunit NR1 to determine whether or not postsynaptic shifts in receptors might also be occurring in the context of aging that would further impact the functional status of the entorhinal inputs to dentate gyrus and CA3 (Adams et al., 1999). Interestingly, there was no statistically significant decrease in NR1 directly associated with age-related memory impairment. However, there was a positive correlation between performance on the Morris water maze and NR1 fluorescence intensity levels regardless of age, and this correlation was present only in CA3. AMPA receptors did not show such a correlation.
Could performance on a memory task be so clearly linked to one particular GluR in a small subset of hippocampal circuits? Clearly, it is too early to draw any causal inference from these data; however, recent transgenic mouse experiments support the notion of a direct relationship between the NMDA receptor proteins and memory performance. First, mice that have the NR1 gene knocked out in a manner that is confined to the hippocampus have impaired learning and memory performance (Tsien et al., 1996). In addition, mice that have a different NMDA receptor subunit, NR2B, overexpressed in the forebrain display enhanced memory and learning in several behavioral paradigms (Tang et al., 1999).
Clearly, these data represent a powerful example of gene/circuit/behavior links that will help to illuminate the role of the NMDA receptor in the hippocampus in age-related memory decline, and they further reinforce the power of multidisciplinary approaches as we move forward in our investigations of the neurobiology of aging. These latter experiments in mice also demonstrate the power of genetically manipulated mice as models for the investigation of memory and, potentially, age-related memory impairment. The required mouse genetics is sufficiently advanced; however, mouse neurophysiology, neuropsychology, and neuroanatomy lag far behind, making detailed interdisciplinary analyses difficult. With respect to mouse neuroanatomy, an important goal for the future will be to develop the quantitative datasets that will link gene products with specific circuits so that genetic manipulations that