Selective Changes in Thin Spine Density and Morphology in Monkey Prefrontal Cortex Correlate with Aging-Related Cognitive Impairment

Abstract

Age-associated memory impairment (AAMI) occurs in many mammalian species, including humans. In contrast to Alzheimer's disease (AD), in which circuit disruption occurs through neuron death, AAMI is due to circuit and synapse disruption in the absence of significant neuron loss and thus may be more amenable to prevention or treatment. We have investigated the effects of aging on pyramidal neurons and synapse density in layer III of area 46 in dorsolateral prefrontal cortex of young and aged, male and female rhesus monkeys (Macaca mulatta) that were tested for cognitive status through the delayed non-matching-to-sample (DNMS) and delayed response tasks. Cognitive tests revealed an age-related decrement in both acquisition and performance on DNMS. Our morphometric analyses revealed both an age-related loss of spines (33%, p < 0.05) on pyramidal cells and decreased density of axospinous synapses (32%, p < 0.01) in layer III of area 46. In addition, there was an age-related shift in the distribution of spine types reflecting a selective vulnerability of small, thin spines, thought to be particularly plastic and linked to learning. While both synapse density and the overall spine size average of an animal were predictive of number of trials required for acquisition of DNMS (i.e., learning the task), the strongest correlate of behavior was found to be the head volume of thin spines, with no correlation between behavior and mushroom spine size or density. No synaptic index correlated with memory performance once the task was learned.