Stability of Postsynaptic Density Size in Hippocampal Synapses of Aged Rats with Preserved but not with Impaired Spatial Learning

Another research strategy for defining structural synaptic correlates of learning is to compare patterns of synaptic ultrastructure in aged animals with preserved or impaired learning capacities. Although a cardinal feature of normal aging is a decline in learning and memory, it has long been noted that some aged individuals exhibit preserved cognitive functions even at advanced chronological ages. It has been demonstrated with unbiased stereological techniques that deficits in hippocampus-dependent spatial learning observed in a subpopulation of aged rats are not associated with a loss of principal hippocampal neurons43,44 or synapses involving them45. In the absence of neuronal and synaptic loss, age-related spatial learning impairments may be caused by structural modifications of existing synapses. The validity of this supposition was tested in our study46 evaluating whether age-related deficits in spatial learning are associated with a reduction of PSD area in hippocampal axospinous synapses because such a structural modification is likely to have a deleterious effect on excitatory synaptic transmission. A hippocampus-dependent version of the Morris water maze task was used to behaviorally characterize aged (27-month-old) rats and to separate them into learning-unimpaired and learning-impaired groups. Additionally, young adult (6-month-old) rats with good spatial learning were studied. Brain tissue was collected 4 weeks after the completion of the behavioral testing. A pilot experiment using different aged rats showed that their performance on the Morris water maze task was the same (either preserved or impaired) over a period of 4 weeks. Axospinous synapses were analyzed in the CA1 stratum radiatum, and unbiased estimates of PSD area in perforated and nonperforated synaptic junctions were obtained as described25. The major finding of this study is that a marked (~30%)

and significant decrease in PSD area occurs in perforated synapses of aged learning-impaired rats relative to both their aged learning-unimpaired counterparts and young adults. This change involves a substantial proportion of perforated synapses, regardless of whether they exhibit a fenestrated, horseshoe-shaped or segmented PSD, but it is not detected in nonperforated synapses.

The area of perforated PSDs positively correlates with the content of postsynaptic AMPARs in axospinous synapses from the rat CA1 stratum radiatum11,39, and it is conceivable that the observed reduction of perforated PSD area in aged learning-impaired rats may result from a diminished AMPAR expression. Provided a significant proportion of perforated synapses indeed express only a few AMPARs, this would render such synaptic contacts less efficient and hence contribute to the age-related cognitive decline. Conversely, the size stability of perforated PSDs in aged learning-unimpaired rats, which reflects the retention of the full complement of postsynaptic AMPARs, appears to be a prerequisite for the maintenance of normal mnemonic functions during aging.

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