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The ageing cortical synapse: hallmarks and implications for cognitive decline

Key Points

  • 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.

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.

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Figure 1: Cortical neuron spines in young and aged non-human primates.
Figure 2: Delayed non-matching-to-sample acquisition correlates with synaptic indices.
Figure 3: Age-related changes in firing of prefrontal neurons during a working memory task.
Figure 4: Age-related changes in the synaptic characteristics of monkey dentate gyrus axonal boutons.
Figure 5: Schematic representation of age and oestradiol effects on spines and cognition in monkeys.

References

  1. 1

    Goldman-Rakic, P. S. Topography of cognition: parallel distributed networks in primate association cortex. Annu. Rev. Neurosci. 11, 137–156 (1988).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Goldman-Rakic, P. S. Cellular basis of working memory. Neuron 14, 477–485 (1995).

    CAS  Article  Google Scholar 

  3. 3

    Miller, E. K. The prefrontal cortex and cognitive control. Nature Rev. Neurosci. 1, 59–65 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Fuster, J. M. The Prefrontal Cortex. 4th edn (Academic Press, London, 2008). This book provides an authoritative and comprehensive analysis of the unique role of the PFC in cognition.

    Book  Google Scholar 

  5. 5

    Rapp, P. R. & Amaral, D. G. Evidence for task-dependent memory dysfunction in the aged monkey. J. Neurosci. 9, 3568–3576 (1989).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Rapp, P. R. Visual discrimination and reversal learning in the aged monkey (Macaca mulatta). Behav. Neurosci. 104, 876–884 (1990).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Herndon, J. G., Moss, M. B., Rosene, D. L. & Killiany, R. J. Patterns of cognitive decline in aged rhesus monkeys. Behav. Brain Res. 87, 25–34 (1997). This paper reports a cross-sectional study of performance ona battery of multiple behavioural tasks across the lifespan of rhesus monkeys.

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Moore, T. L., Killiany, R. J., Herndon, J. G., Rosene, D. L. & Moss, M. B. Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol. Aging 27, 1484–1493 (2006).

    Article  PubMed  Google Scholar 

  9. 9

    Voytko, M. L. Impairments in acquisition and reversals of two-choice discriminations by aged rhesus monkeys. Neurobiol. Aging 20, 617–627 (1999).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Lyons-Warren, A., Lillie, R. & Hershey, T. Short- and long-term spatial delayed response performance across the lifespan. Dev. Neuropsychol. 26, 661–678 (2004).

    Article  PubMed  Google Scholar 

  11. 11

    Arnsten, A. F., Paspalas, C. D., Gamo, N. J., Yang, Y. & Wang, M. Dynamic network connectivity: a new form of neuroplasticity. Trends Cogn. Sci. 14, 365–375 (2010). This paper summarizes research on mechanisms of plasticity, which underlie spatial working memory function in the PFC.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Peters, A., Morrison, J. H., Rosene, D. L. & Hyman, B. T. Feature article: are neurons lost from the primate cerebral cortex during normal aging? Cereb. Cortex 8, 295–300 (1998).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Smith, D. E., Rapp, P. R., McKay, H. M., Roberts, J. A. & Tuszynski, M. H. Memory impairment in aged primates is associated with focal death of cortical neurons and atrophy of subcortical neurons. J. Neurosci. 24, 4373–4381 (2004).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Alexander, G. E. et al. Age-related regional network of magnetic resonance imaging gray matter in the rhesus macaque. J. Neurosci. 28, 2710–2718 (2008).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Shamy, J. L. et al. Volumetric correlates of spatiotemporal working and recognition memory impairment in aged rhesus monkeys. Cereb. Cortex 21, 1559–1573 (2011).

    Article  PubMed  Google Scholar 

  16. 16

    Peters, A., Sethares, C. & Luebke, J. I. Synapses are lost during aging in the primate prefrontal cortex. Neuroscience 152, 970–981 (2008). This paper was the first quantitative electron microscopic study to report synapse loss in the rhesus monkey PFC and to show that the degree of synapse loss in layer 2/3 correlates with cognitive impairment.

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Dumitriu, D. et al. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J. Neurosci. 30, 7507–7515 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Duan, H. et al. Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys. Cereb. Cortex 13, 950–961 (2003).

    Article  PubMed  Google Scholar 

  19. 19

    Luebke, J., Barbas, H. & Peters, A. Effects of normal aging on prefrontal area 46 in the rhesus monkey. Brain Res. Rev. 62, 212–232 (2010).

    Article  PubMed  Google Scholar 

  20. 20

    Peters, A. & Sethares, C. Aging and the myelinated fibers in prefrontal cortex and corpus callosum of the monkey. J. Comp. Neurol. 442, 277–291 (2002).

    Article  PubMed  Google Scholar 

  21. 21

    Peters, A. in Brain Aging: Models, Methods, and Mechanisms (ed. Riddle, D. R.) (CRC Press, North Carolina, 2007).

    Google Scholar 

  22. 22

    Chang, Y. M., Rosene, D. L., Killiany, R. J., Mangiamele, L. A. & Luebke, J. I. Increased action potential firing rates of layer 2/3 pyramidal cells in the prefrontal cortex are significantly related to cognitive performance in aged monkeys. Cereb. Cortex 15, 409–418 (2005).

    Article  PubMed  Google Scholar 

  23. 23

    Luebke, J. I. & Chang, Y. M. Effects of aging on the electrophysiological properties of layer 5 pyramidal cells in the monkey prefrontal cortex. Neuroscience 150, 556–562 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Luebke, J. I. & Amatrudo, J. M. Age-related increase of sIAHP in prefrontal pyramidal cells of monkeys: relationship to cognition. Neurobiol. Aging 19 Aug 2010 (doi: 10.1016/j.neurobiolaging.2010.07.002).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Peters, A. & Kaiserman-Abramof, I. R. The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines. Am. J. Anat. 127, 321–355 (1970).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Harris, K. M. & Kater, S. B. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu. Rev. Neurosci. 17, 341–371 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nature Neurosci. 4, 1086–1092 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Kasai, H., Matsuzaki, M., Noguchi, J., Yasumatsu, N. & Nakahara, H. Structure-stability-function relationships of dendritic spines. Trends Neurosci. 26, 360–368 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Zuo, Y., Lin, A., Chang, P. & Gan, W. B. Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Holtmaat, A., Wilbrecht, L., Knott, G. W., Welker, E. & Svoboda, K. Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 441, 979–983 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Bourne, J. & Harris, K. M. Do thin spines learn to be mushroom spines that remember? Curr. Opin. Neurobiol. 17, 381–386 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Kasai, H. et al. Learning rules and persistence of dendritic spines. Eur. J. Neurosci. 32, 241–249 (2010).

    Article  PubMed  Google Scholar 

  33. 33

    Ganeshina, O., Berry, R. W., Petralia, R. S., Nicholson, D. A. & Geinisman, Y. Differences in the expression of AMPA and NMDA receptors between axospinous perforated and nonperforated synapses are related to the configuration and size of postsynaptic densities. J. Comp. Neurol. 468, 86–95 (2004).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Nicholson, D. A. et al. Distance-dependent differences in synapse number and AMPA receptor expression in hippocampal CA1 pyramidal neurons. Neuron 50, 431–442 (2006).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Nicholson, D. A. & Geinisman, Y. Axospinous synaptic subtype-specific differences in structure, size, ionotropic receptor expression, and connectivity in apical dendritic regions of rat hippocampal CA1 pyramidal neurons. J. Comp. Neurol. 512, 399–418 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Busetto, G., Higley, M. J. & Sabatini, B. L. Developmental presence and disappearance of postsynaptically silent synapses on dendritic spines of rat layer 2/3 pyramidal neurons. J. Physiol. 586, 1519–1527 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Zito, K., Scheuss, V., Knott, G., Hill, T. & Svoboda, K. Rapid functional maturation of nascent dendritic spines. Neuron 61, 247–258 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Dumitriu, D., Rodriguez, A. & Morrison, J. H. High-throughput, detailed, cell-specific neuroanatomy of dendritic spines using microinjection and confocal microscopy. Nature Protoc. 6, 1391–1411 (2011).

    CAS  Article  Google Scholar 

  39. 39

    Rodriguez, A., Ehlenberger, D. B., Hof, P. R. & Wearne, S. L. Rayburst sampling, an algorithm for automated three-dimensional shape analysis from laser scanning microscopy images. Nature Protoc. 1, 2152–2161 (2006).

    CAS  Article  Google Scholar 

  40. 40

    Rodriguez, A., Ehlenberger, D. B., Dickstein, D. L., Hof, P. R. & Wearne, S. L. Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS ONE 3, e1997 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Bloss, E. B., Janssen, W. G., McEwen, B. S. & Morrison, J. H. Interactive effects of stress and aging on structural plasticity in the prefrontal cortex. J. Neurosci. 30, 6726–6731 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Bloss, E. B. et al. Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. J. Neurosci. 31, 7831–7839 (2011). Ageing in rats is associated with impaired dendritic spine recovery in the PFC after chronic stress. This supports the view that in addition to age-related changes in spine density and morphology, ageing is also associated with a reduction in the plasticity of dendritic spines.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Kramer, A. F., Bherer, L., Colcombe, S. J., Dong, W. & Greenough, W. T. Environmental influences on cognitive and brain plasticity during aging. J. Gerontol. A Biol. Sci. Med. Sci. 59, M940–M957 (2004).

    Article  PubMed  Google Scholar 

  44. 44

    Horton S., Baker, J. & Schorer J. Expertise and aging: maintaining skills through the lifespan. Eur. Rev. Aging Phys. Act. 5, 89–96 (2008).

    Article  Google Scholar 

  45. 45

    Wang, M. et al. Neuronal basis of age-related working memory decline. Nature 476, 210–213 (2011). This paper directly demonstrates a neurophysiological mechanism for age-related impairments in prefrontal-dependent spatial working memory: a reduction in the firing rate of cells that are active during the memory delay. This physiological deficit could be reversed by inhibition of cAMP signalling, or by blocking particular subtypes of potassium channels.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Wang, M. et al. α2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129, 397–410 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Chen, S., Wang, J. & Siegelbaum, S. A. Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol. 117, 491–504 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Arnsten, A. F., Cai, J. X. & Goldman-Rakic, P. S. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J. Neurosci. 8, 4287–4298 (1988).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Brown, V. J. & Bowman, E. M. Rodent models of prefrontal cortical function. Trends Neurosci. 25, 340–343 (2002).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Preuss, T. Do rats have prefrontal cortex? J. Cogn. Neurosci. 7, 1–24 (1995).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Barense, M. D., Fox, M. T. & Baxter, M. G. Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats. Learn. Mem. 9, 191–201 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Ramos, B. P. et al. Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 40, 835–845 (2003).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Taylor, J. R., Birnbaum, S., Ubriani, R. & Arnsten, A. F. Activation of cAMP-dependent protein kinase A in prefrontal cortex impairs working memory performance. J. Neurosci. 19, RC23 (1999).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Stranahan, A. M., Jiam, N. T., Stocker, A. M. & Gallagher, M. Aging reduces total neuron number in the dorsal component of the rodent prefrontal cortex. J. Comp. Neurol. 20 Oct 2011 (doi:10.1002/cne.22790).

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Liston, C. et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J. Neurosci. 26, 7870–7874 (2006).

    CAS  Article  Google Scholar 

  56. 56

    Radley, J. J. et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 125, 1–6 (2004).

    CAS  Article  Google Scholar 

  57. 57

    Radley, J. J. et al. Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J. Comp. Neurol. 507, 1141–1150 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Cook, S. C. & Wellman, C. L. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J. Neurobiol. 60, 236–248 (2004).

    Article  PubMed  Google Scholar 

  59. 59

    Radley, J. J. et al. Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress. Exp. Neurol. 196, 199–203 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Goldwater, D. S. et al. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience 164, 798–808 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Murray, E. A. & Mishkin, M. Severe tactual as well as visual memory deficits follow combined removal of the amygdala and hippocampus in monkeys. J. Neurosci. 4, 2565–2580 (1984).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Meunier, M., Bachevalier, J., Mishkin, M. & Murray, E. A. Effects on visual recognition of combined and separate ablations of the entorhinal and perirhinal cortex in rhesus monkeys. J. Neurosci. 13, 5418–5432 (1993).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Baxter, M. G. & Murray, E. A. Opposite relationship of hippocampal and rhinal cortex damage to delayed nonmatching-to-sample deficits in monkeys. Hippocampus 11, 61–71 (2001).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Morris, R. G., Garrud, P., Rawlins, J. N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Gallagher, M. & Nicolle, M. M. Animal models of normal aging: Relationship between cognitive decline and markers in hippocampal circuitry. Behav. Brain Res. 57, 155–162 (1993).

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Tulving, E. & Markowitsch, H. J. Episodic and declarative memory: role of the hippocampus. Hippocampus 8, 198–204 (1998).

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Robitsek, R. J., Fortin, N. J., Koh, M. T., Gallagher, M. & Eichenbaum, H. Cognitive aging: a common decline of episodic recollection and spatial memory in rats. J. Neurosci. 28, 8945–8954 (2008). Estimates of hippocampal-dependent episodic recollection were derived from performance in an olfactory recognition task in young and aged rats. These correlated strongly with spatial memory in the water maze: aged rats with spatial memory impairments demonstrated a selective impairment in episodic recollection.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Baxter, M. G. “I've seen it all before”: explaining age-related impairments in object recognition. Theoretical comment on Burke. et al. (2010). Behav. Neurosci. 124, 706–709 (2010).

    Article  PubMed  Google Scholar 

  69. 69

    Burke, S. N. & Barnes, C. A. Senescent synapses and hippocampal circuit dynamics. Trends Neurosci. 33, 153–161 (2010). This paper provides a comprehensive review of age-related alterations in synaptic physiology in the hippocampus and their potential contribution to cognitive decline.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Rapp, P. R. & Gallagher, M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc. Natl Acad. Sci. USA 93, 9926–9930 (1996). This paper reports rigorous, quantitative evidence that neuron loss does not accompany age-related cognitive decline, reinforcing the search for structural and functional alterations short of neuron death that lead to cognitive decline.

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Rapp, P. R., Deroche, P. S., Mao, Y. & Burwell, R. D. Neuron number in the parahippocampal region is preserved in aged rats with spatial learning deficits. Cereb. Cortex 12, 1171–1179 (2002).

    Article  PubMed  Google Scholar 

  72. 72

    Merrill, D. A., Chiba, A. A. & Tuszynski, M. H. Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats. J. Comp. Neurol. 438, 445–456 (2001).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Shamy, J. L. et al. Hippocampal volume is preserved and fails to predict recognition memory impairment in aged rhesus monkeys (Macaca mulatta). Neurobiol. Aging 27, 1405–1415 (2006).

    Article  PubMed  Google Scholar 

  74. 74

    Gazzaley, A. H., Thakker, M. M., Hof, P. R. & Morrison, J. H. Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys. Neurobiol. Aging 18, 549–553 (1997).

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Merrill, D. A., Roberts, J. A. & Tuszynski, M. H. Conservation of neuron number and size in entorhinal cortex layers, II, III, and V/VI of aged primates. J. Comp. Neurol. 422, 396–401 (2000).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    De Leon, M. J. et al. Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease. Neurobiol. Aging 18, 1–11 (1997).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Gomez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16, 4491–4500 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Rusinek, H. et al. Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MR imaging study of normal aging. Radiology 229, 691–696 (2003).

    Article  PubMed  Google Scholar 

  79. 79

    Calhoun, M. E. et al. Age-related spatial learning impairment is unrelated to spinophilin immunoreactive spine number and protein levels in rat hippocampus. Neurobiol. Aging 29, 1256–1264 (2008).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Geinisman, Y. et al. Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum. Neurobiol. Aging 25, 407–416 (2004).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Scheff, S. W., Price, D. A., Schmitt, F. A., DeKosky, S. T. & Mufson, E. J. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68, 1501–1508 (2007).

    CAS  Article  PubMed  Google Scholar 

  82. 82

    Nicholson, D. A., Yoshida, R., Berry, R. W., Gallagher, M. & Geinisman, Y. Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J. Neurosci. 24, 7648–7653 (2004). This is one of the more recent papers in an important series of publications highlighting the fact that subtle synaptic alterations revealed by careful quantitative analysis can lead to age-related cognitive decline.

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Smith, T. D., Adams, M. M., Gallagher, M., Morrison, J. H. & Rapp, P. R. Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J. Neurosci. 20, 6587–6593 (2000).

    CAS  Article  PubMed  Google Scholar 

  84. 84

    Adams, M. M. et al. Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction. Neuroscience 171, 373–382 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Geinisman, Y., de Toledo-Morrell, L., Morrell, F., Persina, I. S. & Rossi, M. Age-related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique. Hippocampus 2, 437–444 (1992).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Geinisman, Y., de Toledo-Morrell, L. & Morrell, F. Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. Proc. Natl Acad. Sci. USA 83, 3027–3031 (1986).

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Morrison, J. H. & Hof, P. R. Life and death of neurons in the aging brain. Science 278, 412–419 (1997).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Hara, Y. et al. Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys. Neurobiol. Aging 33, 421 (2012).

    Article  PubMed  Google Scholar 

  89. 89

    Hara, Y. et al. Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J. Neurosci. 31, 7737–7744 (2011). Using serial-section electron microscopy, this study demonstrated relationships between a reduction in multiple-synapse boutons and age-related cognitive impairment in rhesus monkeys.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Shi, L., Adams, M. & Brunso-Bechtold, J. K. in Brain Aging: Models, Methods, and Mechanisms Ch. 8 (ed. Riddle, D. R.) (CRC Press, North Carolina, 2007).

    Google Scholar 

  91. 91

    Haberman, R. P. et al. Prominent hippocampal CA3 gene expression profile in neurocognitive aging. Neurobiol. Aging 32, 1678–1692 (2011).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Wilson, I. A., Ikonen, S., Gallagher, M., Eichenbaum, H. & Tanila, H. Age-associated alterations of hippocampal place cells are subregion specific. J. Neurosci. 25, 6877–6886 (2005).

    CAS  Article  PubMed  Google Scholar 

  93. 93

    Goosens, K. A. & Sapolsky, R. M. in Brain Aging: Models, Methods, and Mechanisms (ed. Riddle, D. R.) (CRC Press, North Carolina, 2007).

    Google Scholar 

  94. 94

    McEwen, B. S. Sex, stress and the hippocampus: allostasis, allostatic load and the aging process. Neurobiol. Aging 23, 921–939 (2002).

    CAS  Article  Google Scholar 

  95. 95

    Bloss, E. B., Morrison, J. H. & McEwen, B. S. in The Handbook of Stress: Neuropsychological Effects on the Brain 1st edn Ch. 17 (ed. Conrad, C. D.), (Wiley-Blackwell, Oxford, 2011).

    Google Scholar 

  96. 96

    Merrill, D. A., Karim, R., Darraq, M., Chiba, A. A. & Tuszynski, M. H. Hippocampal cell genesis does not correlate with spatial learning ability in aged rats. J. Comp. Neurol. 459, 201–207 (2003).

    Article  PubMed  Google Scholar 

  97. 97

    Bizon, J. L. & Gallagher, M. Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline. Eur. J. Neurosci. 18, 215–219 (2003).

    CAS  Article  PubMed  Google Scholar 

  98. 98

    Drapeau, E. et al. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl Acad. Sci. USA 100, 14385–14390 (2003).

    CAS  Article  PubMed  Google Scholar 

  99. 99

    Bizon, J. L. & Gallagher, M. More is less: neurogenesis and age-related cognitive decline in Long-Evans rats. Sci. Aging Knowledge Environ. 16 Feb 2005 (doi: 10.1126/sageke.2005.7.re2).

    Article  PubMed  Google Scholar 

  100. 100

    Leuner, B., Kozorovitskiy, Y., Gross, C. G. & Gould, E. Diminished adult neurogenesis in the marmoset brain precedes old age. Proc. Natl Acad. Sci. USA 104, 17169–17173 (2007).

    CAS  Article  PubMed  Google Scholar 

  101. 101

    Aizawa, K., Ageyama, N., Yokoyama, C. & Hisatsune, T. Age-dependent alteration in hippocampal neurogenesis correlates with learning performance of macaque monkeys. Exp. Anim. 58, 403–407 (2009).

    CAS  Article  PubMed  Google Scholar 

  102. 102

    Aizawa, K., Ageyama, N., Terao, K. & Hisatsune, T. Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus. Neurobiol. Aging 32, 140–150 (2011).

    CAS  Article  PubMed  Google Scholar 

  103. 103

    Rosenzweig, E. S. & Barnes, C. A. Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog. Neurobiol. 69, 143–179 (2003).

    CAS  Article  PubMed  Google Scholar 

  104. 104

    Foster, T. C. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell 6, 319–325 (2007).

    CAS  Article  PubMed  Google Scholar 

  105. 105

    Oh, M. M., Oliveira, F. A. & Disterhoft, J. F. Learning and aging related changes in intrinsic neuronal excitability. Front. Aging Neurosci. 2, 2 (2010).

    PubMed  PubMed Central  Google Scholar 

  106. 106

    Geinisman, Y., deToledo-Morrell, L. & Morrell, F. Induction of long-term potentiation is associated with an increase in the number of axospinous synapses with segmented postsynaptic densities. Brain Res. 566, 77–88 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Geinisman, Y., Detoledo-Morrell, L., Morrell, F., Persina, I. S. & Beatty, M. A. Synapse restructuring associated with the maintenance phase of hippocampal long-term potentiation. J. Comp. Neurol. 368, 413–423 (1996).

    CAS  Article  PubMed  Google Scholar 

  108. 108

    Geinisman, Y., Berry, R. W., Disterhoft, J. F., Power, J. M. & Van der Zee, E. A. Associative learning elicits the formation of multiple-synapse boutons. J. Neurosci. 21, 5568–5573 (2001).

    CAS  Article  PubMed  Google Scholar 

  109. 109

    Toni, N. et al. Remodeling of synaptic membranes after induction of long-term potentiation. J. Neurosci. 21, 6245–6251 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Woolley, C. S., Wenzel, H. J. & Schwartzkroin, P. A. Estradiol increases the frequency of multiple synapse boutons in the hippocampal CA1 region of the adult female rat. J. Comp. Neurol. 373, 108–117 (1996).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Arber, S. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805–809 (1998).

    CAS  Article  Google Scholar 

  112. 112

    Yang, N. et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393, 809–812 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Maekawa, M. et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285, 895–898 (1999).

    CAS  Article  Google Scholar 

  114. 114

    Desmond, N. L. & Weinberg, R. J. Enhanced expression of AMPA receptor protein at perforated axospinous synapses. Neuroreport 9, 857–860 (1998).

    CAS  Article  PubMed  Google Scholar 

  115. 115

    Rapp, P. R., Morrison, J. H. & Roberts, J. A. Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J. Neurosci. 23, 5708–5714 (2003). This study demonstrated that a cyclic regimen of oestradiolreplacement to aged, surgically menopausal monkeys was sufficient to preserve their cognitive abilities relative to monkeys that did not receive hormone treatment.

    CAS  Article  PubMed  Google Scholar 

  116. 116

    Shumaker, S. A. et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. Jama 289, 2651–2662 (2003).

    CAS  Article  PubMed  Google Scholar 

  117. 117

    Henderson, V. W. Estrogen-containing hormone therapy and Alzheimer's disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience 138, 1031–1039 (2006).

    CAS  Article  PubMed  Google Scholar 

  118. 118

    Maki, P. M. Hormone therapy and cognitive function: is there a critical period for benefit? Neuroscience 138, 1027–1030 (2006).

    CAS  Article  PubMed  Google Scholar 

  119. 119

    Sherwin, B. B. Estrogen and memory in women: how can we reconcile the findings? Horm. Behav. 47, 371–375 (2005).

    CAS  Article  PubMed  Google Scholar 

  120. 120

    Turgeon, J. L., McDonnell, D. P., Martin, K. A. & Wise, P. M. Hormone therapy: physiological complexity belies therapeutic simplicity. Science 304, 1269–1273 (2004).

    CAS  Article  PubMed  Google Scholar 

  121. 121

    Morrison, J. H., Brinton, R. D., Schmidt, P. J. & Gore, A. C. Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women. J. Neurosci. 26, 10332–10348 (2006).

    CAS  Article  PubMed  Google Scholar 

  122. 122

    Gibbs, R. B. & Gabor, R. Estrogen and cognition: applying preclinical findings to clinical perspectives. J. Neurosci. Res. 74, 637–643 (2003).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    Asthana, S. et al. Frontiers proposal. National Institute on Aging “bench to bedside: estrogen as a case study”. Age 31, 199–210 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Brinton, R. D. Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol. Sci. 30, 212–222 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Sherwin, B. B. Estrogen and cognitive functioning in women: lessons we have learned. Behav. Neurosci. 126, 123–127 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Resnick, S. M. & Henderson, V. W. Hormone therapy and risk of Alzheimer disease: a critical time. Jama 288, 2170–2172 (2002).

    Article  PubMed  Google Scholar 

  127. 127

    Sherwin, B. B. Estrogen and cognitive aging in women. Neuroscience 138, 1021–1026 (2006).

    CAS  Article  PubMed  Google Scholar 

  128. 128

    Sherwin, B. B. Estrogen therapy: is time of initiation critical for neuroprotection? Nature Rev. Endocrinol. 5, 620–627 (2009). This article comprehensively reviews studies on oestrogen supplementation in which information about the timing of therapy was provided, allowing an appraisal of evidence for and against the 'critical period' hypothesis.

    CAS  Article  Google Scholar 

  129. 129

    Zandi, P. P. et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. Jama 288, 2123–2129 (2002).

    CAS  Article  PubMed  Google Scholar 

  130. 130

    Rocca, W. A., Grossardt, B. R. & Shuster, L. T. Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. Brain Res. 1379, 188–198 (2011).

    CAS  Article  PubMed  Google Scholar 

  131. 131

    Adams, M. M., Shah, R. A., Janssen, W. G. & Morrison, J. H. Different modes of hippocampal plasticity in response to estrogen in young and aged female rats. Proc. Natl Acad. Sci. USA 98, 8071–8076 (2001).

    CAS  Article  PubMed  Google Scholar 

  132. 132

    Savonenko, A. V. & Markowska, A. L. The cognitive effects of ovariectomy and estrogen replacement are modulated by aging. Neuroscience 119, 821–830 (2003).

    CAS  Article  PubMed  Google Scholar 

  133. 133

    Adams, M. M. et al. Estrogen and aging affect the subcellular distribution of estrogen receptor-α in the hippocampus of female rats. J. Neurosci. 22, 3608–3614 (2002).

    CAS  Article  PubMed  Google Scholar 

  134. 134

    Okamoto, K., Nagai, T., Miyawaki, A. & Hayashi, Y. Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nature Neurosci. 7, 1104–1112 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Spencer, J. L., Waters, E. M., Milner, T. A. & McEwen, B. S. Estrous cycle regulates activation of hippocampal Akt, LIM kinase, and neurotrophin receptors in C57BL/6 mice. Neuroscience 155, 1106–1119 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Yildirim, M. et al. Estrogen and aging affect synaptic distribution of phosphorylated LIM kinase (pLIMK) in CA1 region of female rat hippocampus. Neuroscience 152, 360–370 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Luine, V., Attalla, S., Mohan, G., Costa, A. & Frankfurt, M. Dietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats. Brain Res. 1126, 183–187 (2006).

    CAS  Article  PubMed  Google Scholar 

  138. 138

    Shansky, R. M. et al. Estrogen promotes stress sensitivity in a prefrontal cortex-amygdala pathway. Cereb. Cortex 20, 2560–2567 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Hao, J. et al. Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys. J. Comp. Neurol. 465, 540–550 (2003).

    CAS  Article  PubMed  Google Scholar 

  140. 140

    Leranth, C., Shanabrough, M. & Redmond, D. E. Gonadal hormones are responsible for maintaining the integrity of spine synapses in the CA1 hippocampal subfield of female nonhuman primates. J. Comp. Neurol. 447, 34–42 (2002).

    CAS  Article  PubMed  Google Scholar 

  141. 141

    Keenan, P. A., Ezzat, W. H., Ginsburg, K. & Moore, G. J. Prefrontal cortex as the site of estrogen's effect on cognition. Psychoneuroendocrinology 26, 577–590 (2001).

    CAS  Article  PubMed  Google Scholar 

  142. 142

    Scheff, S. W., Price, D. A., Schmitt, F. A. & Mufson, E. J. Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol. Aging 27, 1372–1384 (2006). This paper reports quantitative electron microscopy data from human brain showing that there is extensive synapse loss early in the progression of Alzheimer's disease.

    CAS  Article  PubMed  Google Scholar 

  143. 143

    Akram, A. et al. Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer's disease. Neurobiol. Aging 29, 1296–1307 (2008).

    CAS  Article  PubMed  Google Scholar 

  144. 144

    Bell, K. F. & Hardingham, G. E. The influence of synaptic activity on neuronal health. Curr. Opin. Neurobiol. 21, 299–305 (2011). This review highlights the relationship between synaptic events and alterations and the risk of neuron death, a relationship that is likely to be crucially important in the transition from synaptic alterations to Alzheimer's disease in humans.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145

    Jacobsen, J. S. et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 103, 5161–5166 (2006).

    CAS  Article  PubMed  Google Scholar 

  146. 146

    Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neurosci. 8, 1051–1058 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Selkoe, D. J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).

    CAS  Article  Google Scholar 

  148. 148

    Selkoe, D. J. Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–113 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Small, S. A., Schobel, S. A., Buxton, R. B., Witter, M. P. & Barnes, C. A. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nature Rev. Neurosci. 12, 585–601 (2011).

    CAS  Article  Google Scholar 

  150. 150

    Wang, A. C., Hara, Y., Janssen, W. G., Rapp, P. R. & Morrison, J. H. Synaptic estrogen receptor-α levels in prefrontal cortex in female rhesus monkeys and their correlation with cognitive performance. J. Neurosci. 30, 12770–12776 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    Hojo, Y. et al. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons. Proc. Natl Acad. Sci. USA 101, 865–870 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Rune, G. M. & Frotscher, M. Neurosteroid synthesis in the hippocampus: role in synaptic plasticity. Neuroscience 136, 833–842 (2005).

    CAS  Article  PubMed  Google Scholar 

  153. 153

    Lasley, B. L., Crawford, S. & McConnell, D. S. Adrenal androgens and the menopausal transition. Obstet. Gynecol. Clin. North Am. 38, 467–475 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Rapp, P. R. in Handbook of the Neuroscience of Aging (eds Hof, P. R. & Mobbs, C. V.) 235–242 (Academic Press, 2009).

    Google Scholar 

  155. 155

    Gallagher, M., Stocker, A. M. & Koh, M. T. Mindspan: lessons from rat models of neurocognitive aging. ILAR J. 52, 32–40 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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.

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Glossary

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.

Spinophilin

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.

Synaptophysin

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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