Individual differences are a hallmark of cognitive and synaptic ageing. Neurobiological differences between individuals of the same chronological age may underlie the preservation of cognitive abilities in advanced age versus cognitive impairment.
In general, age-related cognitive impairments that occur in the absence of neurodegenerative diseases are not associated with loss of cortical neurons. Instead, they seem to be associated with subtle synaptic alterations.
The prefrontal cortex controls higher-order, complex behaviours. A hallmark of cognitive ageing is impaired prefrontal function, including impairments in spatial working memory.
One synaptic correlate of age-related impairments in working memory that has been identified in monkeys is a loss of thin spines in layer 3 of the dorsolateral prefrontal cortex.
The medial temporal lobe, including the hippocampus, is responsible for memories of everyday events.
Mild impairments in medial temporal lobe function are also observed in cognitive ageing.
A range of synaptic alterations in hippocampal function that correlate with age-related memory impairments have been described. These have been observed in all subfields of the hippocampus and differ between subfields.
A notable synaptic alteration in the aged monkey hippocampus is the loss of multisynaptic boutons in the dentate gyrus, which correlates with cognitive impairments.
Cyclical oestradiol treatment of aged, surgically menopausal monkeys increases the density of thin dendritic spines in the prefrontal cortex and improves working memory. This illustrates the potential of synaptic and cognitive changes in ageing to be reversible.
Loss of synapses may predispose neurons to degeneration in disease states. Thus, a better understanding of mechanisms that promote stability of synapses in ageing should lead not only to amelioration of age-related cognitive impairments but may also affect vulnerability to neurodegenerative diseases.
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.
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We thank Y. Hara, G. Ellis-Davies and E. Bloss for comments on the manuscript. We also thank Y. Hara, D. Dumitriu and B. Janssen for assistance with the figures. Reconstruction and visualization of FIG. 1 was done by our colleagues from TheVisualMD. The authors' research is supported by NIH grants P01-AG016765, R37-AG06647 and R01-AG010606.
The authors declare no competing financial interests.
- Axospinous synapses
Synapses between the axon from one neuron and the dendritic spine of another neuron.
- Delayed non-matching-to-sample
(DNMS). A test of recognition memory, which is commonly used in monkeys. A monkey's memory for a sample object is tested by offering a choice between the sample and a novel object, and the monkey is rewarded for choosing the novel object (non-matching). Performance in this task is dependent on an intact medial temporal lobe.
- Delayed response task
A test of spatiotemporal working memory, which is commonly used in monkeys. A monkey is cued to remember a location in space for a brief interval and then is rewarded for selecting that location at the end of the interval. Performance in this task is dependent on an intact prefrontal cortex.
- Attentional set-shifting task
A test of executive function in which discrimination problems among stimuli with multiple independently variable relevant characteristics (dimensions), such as shape and colour, are presented in succession. Attentional shifting is engaged when the relevant dimension for solving the discrimination problems changes.
A protein that is highly enriched in dendritic spines and that is often used as an immunohistochemical marker of dendritic spines.
- Perforated synapses
Large synapses that are implicated in memory-related plasticity. Perforated synapses are characterized by a discontinuity in the postsynaptic density, resulting in a hole, a slit or a complete segmentation of the postsynaptic density plate.
A synaptic vesicle protein that is highly enriched in synapses and that is often used as an immunohistochemical marker of synapses.
- Lacunosum-moleculare layer
The most superficial layer of the CA1–3 fields of the hippocampus. In CA3, it contains synapses from the perforant path (the projection from the entorhinal cortex to the hippocampus).
- Multisynaptic boutons
Axonal boutons that form synaptic contacts with more than one dendritic spine or shaft. Multisynaptic boutons are implicated in hippocampus-dependent learning.
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Morrison, J., Baxter, M. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13, 240–250 (2012). https://doi.org/10.1038/nrn3200
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