Senescent synapses and hippocampal circuit dynamics

Burke, Sara N.; Barnes, Carol A.

doi:10.1016/j.tins.2009.12.003

Cited by 174 publications

(162 citation statements)

References 92 publications

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“…These results complement the effects on synaptic function, because synaptic processes are also calcium-dependent. We and others have shown that calcium dyshomeostasis plays a key role in brain-aging processes (44,56,71) and have demonstrated that vitamin D reverses calcium-related electrophysiological markers of brain aging (24,27). Together, these results suggest that the effects of vitamin D on calcium regulation and synaptic function may interact to counter cognitive decline with aging.…”

Section: Additional Pathways Potentially Related To Cognitive Functionmentioning

confidence: 61%

“…Compared with the low-and medium-VitD3 groups, the highVitD3 group had a significantly steeper I/O slope. These results suggest that high VitD3 may improve neuronal excitability, which is known to decrease with age (44). However, this increased (Table 1) to an approximate twofold increase in 25OHD.…”

Section: Significancementioning

confidence: 81%

“…A common feature of brain aging is a decrease in synaptic strength or impaired communication between neurons (32,44,(55)(56)(57)(58). Synaptic connections become dysfunctional, perhaps in part as a result of reduced vesicle trafficking and neurotransmitter release, causing diminished plasticity (56,(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

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Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Latimer¹,

Brewer²,

Searcy³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

181

103

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Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate agerelated cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 mo, middle-aged F344 rats were fed diets containing low, medium (typical amount), or high (100, 1,000, or 10,000 international units/kg diet, respectively) vitamin D3, and hippocampal-dependent learning and memory were then tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication, and G protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced, corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function, and they suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.V itamin D, a secosteroid hormone known for its role in bone and calcium homeostasis, is now well recognized for its many diverse functions and actions on a variety of tissues and cell types (1, 2). Vitamin D typically refers to the precursor forms of the hormone obtained through the skin's exposure to sunlight [vitamin D3 (VitD3)] or from dietary sources (VitD3 or VitD2). A metabolite of vitamin D, 25-hydroxyvitamin D (25OHD), is a serum biomarker of vitamin D status or repletion. In recent years, there is particular concern that large segments of the population may have low levels of 25OHD, and therefore are vitamin D-deficient (3). Due to factors such as reduced intake, absorption, and decreased exposure to sunlight, aging adults (≥50 y of age) are especially susceptible (3-6). Notably, this predisposition for lower 25OHD levels in the elderly has been linked to higher risk for numerous age-related disorders, including cancer and metabolic and vascular diseases (7-10).Inadequate vitamin D status also correlates with a greater risk for cognitive decline in the elderly (4,(11)(12)(13)(14)(15), suggesting that optimal levels may promote healthy brain aging (16,17). Because the brain expresses vitamin D receptors (VDRs) and can synthesize the active form of the hormone, the possible cognitive enhancing effects of vitamin D may reflect a primary action in the brain rather than a result of secondary systemic effects (18)(19)(20)(21)(22). Indeed, we and others have shown that vitamin D, as ...

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Section: Additional Pathways Potentially Related To Cognitive Functionmentioning

confidence: 61%

Section: Significancementioning

confidence: 81%

See 1 more Smart Citation

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Latimer¹,

Brewer²,

Searcy³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

181

103

View full text Add to dashboard Cite

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“…There is significant evidence suggesting that synaptic impairment, rather than neuronal loss, may be the leading cause of cognitive deterioration (1)(2)(3). However, the mechanisms that underlie this synaptic impairment remain poorly understood.…”

mentioning

confidence: 99%

“…It is widely believed that learning deficits within the aging brain result from reduced synaptic density and plasticity (3). Most studies so far have focused on dendritic spines, the postsynaptic sites of excitatory synapses.…”

mentioning

confidence: 99%

Increased axonal bouton dynamics in the aging mouse cortex

Grillo

Song

Ruivo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

100

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Aging is a major risk factor for many neurological diseases and is associated with mild cognitive decline. Previous studies suggest that aging is accompanied by reduced synapse number and synaptic plasticity in specific brain regions. However, most studies, to date, used either postmortem or ex vivo preparations and lacked key in vivo evidence. Thus, whether neuronal arbors and synaptic structures remain dynamic in the intact aged brain and whether specific synaptic deficits arise during aging remains unknown. Here we used in vivo two-photon imaging and a unique analysis method to rigorously measure and track the size and location of axonal boutons in aged mice. Unexpectedly, the aged cortex shows circuit-specific increased rates of axonal bouton formation, elimination, and destabilization. Compared with the young adult brain, large (i.e., strong) boutons show 10-fold higher rates of destabilization and 20-fold higher turnover in the aged cortex. Size fluctuations of persistent boutons, believed to encode long-term memories, also are larger in the aged brain, whereas bouton size and density are not affected. Our data uncover a striking and unexpected increase in axonal bouton dynamics in the aged cortex. The increased turnover and destabilization rates of large boutons indicate that learning and memory deficits in the aged brain arise not through an inability to form new synapses but rather through decreased synaptic tenacity. Overall our study suggests that increased synaptic structural dynamics in specific cortical circuits may be a mechanism for agerelated cognitive decline.neural circuits | ageing | structural plasticity | axon | in vivo imaging W hat are the cellular mechanisms that lead to age-related cognitive decline? There is significant evidence suggesting that synaptic impairment, rather than neuronal loss, may be the leading cause of cognitive deterioration (1-3). However, the mechanisms that underlie this synaptic impairment remain poorly understood.It is widely believed that learning deficits within the aging brain result from reduced synaptic density and plasticity (3). Most studies so far have focused on dendritic spines, the postsynaptic sites of excitatory synapses. Both the size and the number of dendritic spines are affected in pyramidal neurons of the aged (Ag) cortex and hippocampus (2-5). Interestingly, it is mainly thin spines, likely to be the main site of postsynaptic plasticity (6), that are reduced in numbers and display a larger spine head volume in cortical neurons of the Ag monkey (7) and in rat cortex (8). Much less is known about presynaptic deficits with aging. Synaptophysin (a synaptic vesicle component) labeling decreases (9), and treatments that rescue age-related cognitive decline lead to increased synaptophysin immunoreactivity and increased synaptic plasticity in the hippocampus (10). Overall these findings from different brain areas and species point to a reduction of the number, size, and plasticity of neuronal connections in the Ag brain. However, most studies to date h...

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Normal Neurocognitive Aging

Fletcher

Rapp

2012

Handbook of Psychology, Second Edition

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The Neurocognitive Study for the Aging (NEUROAGE) was formally established in 2009 with initial funding by the Cyprus Research Promotion Foundation. It is a longitudinal prospective project with a rolling admission process. NEUROAGE aims to investigate cognitive processes such as memory, concentration, speed of information processing, language abilities and executive skills in a large sample of Cypriots (N > 800) who are native speakers of Greek (including the Cypri-

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Senescent synapses and hippocampal circuit dynamics

Cited by 174 publications

References 92 publications

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Increased axonal bouton dynamics in the aging mouse cortex

Normal Neurocognitive Aging

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