Synapses are lost during aging in the primate prefrontal cortex

Abstract

An electron microscopic analysis has been carried out on the effects of age on the numerical density of both excitatory (asymmetric) and inhibitory (symmetric) synapses in the neuropil of layers 2/3 and of layer 5 in area 46 from the frontal cortex of behaviorally tested rhesus monkeys. There is no change in the lengths of synaptic junctions with age or in the percentage distribution of synapses relative to the postsynaptic spines and dendritic shafts. However, in layers 2/3 there is an overall loss of about 30% of synapses from 5 to 30 years of age, and both asymmetric and symmetric synapses are lost at the same rate. In layer 5 the situation is different; the overall loss of synapses is only 20% and this is almost entirely due to a loss of asymmetric synapses, since there is no significant loss of symmetric synapses from this layer with age. When the synapse data are correlated with the overall cognitive impairment shown by the monkeys, it is found that there is a strong correlation between the numerical density of asymmetric synapses in layers 2/3 and cognitive impairment, with a weaker correlation between symmetric synapse loss and cognitive impairment. In layer 5 on the other hand there is no correlation between synapse loss and cognitive impairment. However synapse loss is not the only factor causing cognitive impairment, since in previous studies of area 46 we have found that age-related alteration in myelin in this frontal area also significantly contributes to cognitive decline. The synapse loss is also considered in light of earlier studies, which show that the frequency of spontaneous excitatory synaptic responses is reduced with age in layers 2/3 neurons.

Fig. 1

Electron micrographs of the neuropil in layer 5 of area 46 to show the types of synapses present. For a more complete description of these micrographs see the Results section. (a) The field contains two dendritic spines. One of the spines (sp₁) is forming an asymmetric synapse with an axon terminal (A₁) containing round synaptic vesicles. The other spine (sp₂) is synapsing with one axon terminal (A₂) forming an asymmetric synapse and a second axon terminal (S₂) with pleomorphic vesicles forming a symmetric synapse. Also in this field are a dendrite (d₃) forming an asymmetric synapse with an axon terminal (A₃) containing round vesicles, and a dendrite (d₄) forming an asymmetric synapse with a terminal (A₄) containing round vesicles. The junction (arrow) between the two components of this synapse is sectioned obliquely. (b) On the left of this field is a transversely sectioned dendrite (d₁) forming an asymmetric synapse with an axon terminal (A₁) containing round synaptic vesicles, and a symmetric synapse with an axon terminal (S₁) containing pleomorphic vesicles. Another axon terminal (A₂) is forming an asymmetric synapse with the shaft of a second dendrite (d₂). Also present in the field is a dendritic spine (sp₃) forming an asymmetric synapse with an axon terminal (A₃). The axon terminal and the synaptic junction (arrow) are both sectioned obliquely. There is also a second asymmetric axospinous synapse between an axon terminal (A₄) a dendritic spine (sp₄) in the field. Terminal (A₄) also synapses with dendrite (d₂).

Fig. 2

A plot of the number of asymmetric and symmetric synapses present per mm³ in the neuropil of layers 2/3 against age. The dashed line superimposed on the plot for asymmetric synapses is the piecewise analysis, which shows that most of the loss of these synapses occurs after 20 years of age.

Fig. 3

A plot of the number of asymmetric and symmetric synapses present per mm³ in the neuropil of layer 5 against age. The dashed line superimposed on the plot for asymmetric synapses is the piecewise analysis, which shows that the loss of these synapses with age is gradual.

Fig. 4

A plot of the ratio of the numerical density of asymmetric to symmetric synapses in layers 2/3 and in layer 5 against age.

Fig. 5

A plot of the numerical densities of both asymmetric and symmetric synapses in the neuropil of layers 2/3 against the CII scores attained by the monkeys used in this study.

Fig. 6

A plot of the numerical densities of both asymmetric and symmetric synapses in layer 5 against the CII scores obtained by the monkeys used in this study.