and neurochemical phenotype that would impact function, but not be lethal. This step will require careful quantitative analyses of individual neurons, both in terms of morphometric measures as well as in terms of subcellular analyses of protein distribution patterns. For example, age-related changes in dendritic spine number have been described that could impact neuronal function (Coleman and Flood, 1987), and in fact, in primate neocortex it appears that spine density decreases with age with no change in dendritic length or branching patterns (Duan et al., 1999), and such changes may predominate in the most distal portion of the dendrite (Peters et al., 1998b). In addition, changes in receptor distribution can affect a single portion of the dendritic tree that receives a particular input, leaving the rest of the neuron unaffected (Gazzaley et al., 1996a). Moreover, some age-related changes might preferentially affect the nerve terminal rather than the dendrite, or vice versa. Such subtle changes could profoundly affect circuits and neural transmission with no evidence of generalized cell death.

The Synapse

The highest-resolution morphologic analysis is directed at the synapse and represents a search for potential changes in synapse structure or molecular constituents of the synapse that are related to age and might impact circuit function and behavior. Neocortical synapse loss clearly occurs in Alzheimer's disease and correlates well with degree of cognitive impairment (DeKosky and Scheff, 1990; Terry et al., 1991). High-resolution structural analyses of the synapse suggest that there are synaptic changes in the hippocampus with normal aging in the rat (Geinisman et al., 1995), although such changes may not occur in aged primate (Peters et al., 1996). In addition, the dendritic spine is more plastic than previously thought, and structural changes in the dendritic spine may occur on a time course consistent with induction of changes in synaptic function underlying memory, such as long-term potentiation (Toni et al., 1999). Thus, age-related spine loss or loss of spine plasticity could lead to age-related decline in memory and/or learning.

While purely structural analyses of the aging synapse have been and will continue to be illuminating (Geinisman et al., 1995; Tigges et al., 1996; Peters et al., 1996), perhaps the most exciting applications of electron microscopy to studies of aging will emerge from the use of immunogold postembedding electron microscopy. This immunohistochemical technique has extremely high resolution, in that the molecule of interest is identified by the presence of a discrete gold particle that is 10–25 nanometers in diameter and is highly quantifiable (Chaudhry et al., 1995). In addition, multiple antibodies bound to gold particles of different sizes can be used simultaneously to localize multiple synaptic molecules in a single synapse (He et al., 2000). The number of gold particles can be equated to the number of molecules of the targeted



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