The ageing cortical synapse: hallmarks and implications for cognitive decline

Morrison, John H.; Baxter, Mark G.

doi:10.1038/nrn3200

Cited by 965Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsDementia and Cognitive Impairment Research

The ageing cortical synapse: hallmarks and implications for cognitive decline

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Morrison, John H., Baxter, Mark G.·2012·Nature Reviews Neuroscience

DOI 10.1038/nrn3200PMC PMC3592200

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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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Other chronic stress paradigms cause similar reductions in dendrite complexity and spine density in prefrontal cortex neurons and CA3 pyramidal cells of the hippocampus.
“Other chronic stress paradigms (such as restraint stress) cause similar reductions in dendrite complexity and spine density in PFC neurons and CA3 pyramidal cells of the hippocampus (20–22).”
From Synaptic Dysfunction in Depression: Potential Therapeutic Targets (2012) · cites this paper as [22]
The “Synaptic Aging in the Prefrontal Cortex” section (page unavailable) reports dendritic shrinkage and spine loss after chronic stress in young rat PFC neurons. The “Synaptic Aging in the Hippocampus” section says stress affects hippocampal structure and function, but does not specify reduced dendritic complexity or spine density in CA3 pyramidal cells. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Aging causes weakening and removal of dlPFC synapses on spines.
“Finally, aging causes weakening and removal of dlPFC synapses on spines (Morrison & Baxter, 2012), a process which is worsened by Alzheimer’s Disease (AD), where tau pathology often begins in the medial and ventral areas and moves to dlPFC as the disease progresses, correlating with the rise in dementia (Bussière et al., 2003).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Morrison & Baxter, 2012
The ‘Synaptic Aging in the Prefrontal Cortex’ section reports age-related loss of axospinous synapses in rhesus monkey dlPFC, particularly those on thin spines. It does not establish that the remaining spine synapses weaken; reduced plasticity associated with spine loss is not the same finding. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Gray matter volume decrease is not necessarily correlated with a loss of neurons or synaptic density decrease (as measured by 11C-UCB-J).
“Gray matter volume decrease is well described in aging [42], but it is not necessarily correlated with a loss of neurons [43] or synaptic density decrease (as measured by 11C-UCB-J) [35].”
From Preliminary evidence for preserved synaptic density in late-life depression (2024) · cites this paper as [43]
Studies in rodent models confirm that exposure to stress, like depression, causes atrophy and loss of neurons and glia in the PFC and hippocampus.
“Studies in rodent models have extended these human studies, and confirm that exposure to stress, like depression, causes atrophy and loss of neurons and glia in the PFC and hippocampus1011,12.”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [12]

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[90]Shi L Adams M Brunso-Bechtold JK Subtle Alterations in Glutamatergic Synapses Underlie the Aging-Related Decline in Hippocampal Function NBK3889 [bookaccession] 2007 21204357

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Authors: Morrison, J. H., & Baxter, M. G.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Corresponding author: Morrison, John H.
ORCID: Morrison, John H.
Baxter, Mark G.
Venue: Nature Reviews Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2012-03-07
Volume: 13
Issue: 4
Pages: 240-250
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/nrn3200
PMC: PMC3592200
OpenAlex: W2019249853
Cited by: 965
References: 159
Citations by year: 2026: 72 · 2025: 80 · 2024: 70 · 2023: 87 · 2022: 66 · 2021: 71 · 2020: 96 · 2019: 78 · 2018: 74 · 2017: 52 · 2016: 56 · 2015: 48 · 2014: 50 · 2013: 49 · 2012: 15
FWCI: 5.46
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute on Aging (P01AG016765, R01AG010606, R37‑AG06647, R37AG006647)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: brain aging, synaptic changes, cognitive decline, memory impairment, hippocampus, prefrontal cortex, synaptic plasticity, hormonal status, aged animals
MeSH terms: Aging, Cerebral Cortex, Cognition, Cognition Disorders, Hippocampus, Humans, Neurons, Synapses

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The ageing cortical synapse: hallmarks and implications for cognitive decline

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