The ageing cortical synapse: hallmarks and implications for cognitive decline

Abstract

Normal ageing is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. Here, we review studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals. We also discuss the influence of the hormonal status on these age-related alterations and recent progress in the development of therapeutic strategies to limit the impact of ageing on memory and cognition in humans.

Figure 1. Cortical neuron spines in young and aged non-human primates

Representative examples of Lucifer Yellow-filled prefrontal cortical neurons from young (A) and aged (B) non-human primates. Z-stack tiles of the two neurons were imaged using a Zeiss 510 confocal laser-scanning microscope (CLSM) and rendered into the complete neuronal reconstructions by tiling the entire set of z-stacks. The rectangle identifying a basal dendritic segment in each neuron is shown at higher magnification below each neuron. Note that while the overall dendritic arborization does not diminish with age, the robust spine density present in the young animal is significantly reduced with age, particularly the thin spines (C). Scale bar (low magnification) = 50 μm, scale bar (high magnification) = 10 μm. Image courtesy of theVisualMD.

Figure 2. DNMS acquisition correlates with synaptic indices

A) The scatter plot of DNMS acquisition (trials required to reach 90% accuracy with a 10 second delay) versus EM synaptic density shows a moderate though significant inverse correlation, meaning that higher synaptic density is predictive of faster learning. B) This inverse correlation is somewhat strengthened when the density of only thin spines is used on the subset of animals for which spine density analysis was performed (r=−0.58 in A and r=−0.69 in B; p<0.05 for both). C) DNMS acquisition correlates most strongly with the mean volume of thin spines, where smaller volumes are predictive of faster learning. D) In contrast, no correlation is seen between learning of the DNMS task and mean mushroom head volume. R = Pearson correlation coefficient. (Taken from Figure 8, ref. ^,)

Figure 3. Age-related changes in the response properties of neurons within area 46 of rhesus monkey during a DR task

A) The average firing rate of delay neurons in area 46 recorded in young, middle-aged, and aged monkeys. Blue indicates the firing rate for the preferred direction, and red for the anti-preferred direction. Dark grey background coincides with the time during which the cue is visible and the light grey background designates the delay period. Note that the activity during the delay is decreased in both middle-aged and aged monkeys. B) A schematic of the spines thought to play a key role in WM where the strength of the synapse is modulated by c-AMP-PKA signaling that regulates the activity of HCN and KCNQ channels. This signaling pathway in select synapses is disrupted by aging, and this is thought to occur primarily in thin spines. (A and C taken from Figure 1, ref. ).

Figure 4. Age-related changes in the synaptic characteristics of monkey dentate gyrus axonal boutons

A) Schematic diagrams illustrating the synaptic subtypes in the dentate gyrus that are vulnerable to the effects of aging. Aged monkeys have increased nonsynaptic boutons (NSB), decreased multisynaptic boutons (MSB), and decreased number of synaptic contact per MSB. SSB, single-synaptic bouton. B) A significant inverse correlation is observed between the percentage of NSBs in the monkey dentate gyrus and DNMS average accuracy. Pearson correlation; n=18, r=−0.600, p=0.008.

Figure 5. A schematic representation of the effects of age and estradiol treatment on small spines and cognitive performance in monkeys

The “double hit” of aging and lack of estradiol leads to a dramatic decrease in small spines that leads to cognitive decline. The intermediate spine levels observed in the young ovariectomized (OVX) monkeys treated with vehicle (Veh) and aged OVX monkeys treated with estradiol, along with their sustained performance on the delayed response task, suggests that in the aged OVX+Veh monkeys the number of small spines may fall below the threshold needed to sustain cognitive performance.

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