The ageing cortical synapse: hallmarks and implications for cognitive decline

Morrison, John H.; Baxter, Mark G.

doi:10.1038/nrn3200

Cited by 804 publications

(713 citation statements)

References 151 publications

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“…Studies in rats and non-human primates have demonstrated that aging impairs the functional integrity of prefrontal cortex neurons (Morrison and Baxter 2012) which is associated with decline in structural plasticity and cognitive performance (Dumitriu et al 2010;Bloss et al 2011Bloss et al , 2013. Moreover, studies in human and animal models suggest that age-associated deficits of brain functions are probably more related to alterations in synaptic connectivity and plasticity than with neuronal loss (Gleichmann et al 2012;Sibille 2013;Labarrière et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

Kumar

Thakur

2015

AGE

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Neurexin1 (Nrxn1) and Neuroligin3 (Nlgn3) are cell adhesion proteins, which play an important role in synaptic plasticity that declines with advancing age. However, the expression of these proteins during aging has not been analyzed. In the present study, we have examined the age-related changes in the expression of these proteins in cerebral cortex and hippocampus of 10-, 30-, 50-, and 80-week-old male mice. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis indicated that messenger RNA (mRNA) level of Nrxn1 and Nlgn3 significantly increased from 10 to 30 weeks and then decreased at 50 weeks in both the regions. However, in 80-week-old mice, Nrxn1 and Nlgn3 were further downregulated in cerebral cortex while Nrxn1 was downregulated and Nlgn3 was upregulated in hippocampus. These findings were corroborated by immunoblotting and immunofluorescence results. When the expression of Nrxn1 and Nlgn3 was correlated with presynaptic density marker synaptophysin, it was found that synaptophysin protein expression in cerebral cortex was high at 10 weeks and decreased gradually up to 80 weeks, whereas in hippocampus, it decreased until 50 weeks and then increased remarkably at 80 weeks. Furthermore, Pearson's correlation analysis showed that synaptophysin had a strong relation with Nrxn1 and Nlgn3 in cerebral cortex and with Nlgn3 in hippocampus. Thus, these findings showed that Nrxn1 and Nlgn3 are differentially expressed in cerebral cortex and hippocampus which might be responsible for alterations in synaptic plasticity during aging.

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Section: Introductionmentioning

confidence: 99%

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

Kumar

Thakur

2015

AGE

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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.…”

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confidence: 99%

“…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)(3)(4)(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).…”

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confidence: 99%

Increased axonal bouton dynamics in the aging mouse cortex

Grillo

Song

Ruivo

et al. 2013

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

117

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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“…Studies that employ N-methyl-D-aspartate receptor (NMDAR) antagonists, demonstrate a role for NMDARs in executive function (Stefani and Moghaddam, 2005;Cui et al, 2011;Dalton et al, 2011;Arnsten et al, 2012;Carli and Invernizzi, 2014). Moreover, the decline in executive function during aging is associated with a loss of dendritic spines in the PFC, particularly thin spines that are thought to be involved in NMDAR-mediated synaptic plasticity (Bourne and Harris, 2007;Morrison and Baxter, 2012;Samson and Barnes, 2013). However, it is unclear if NMDAR function in the PFC declines with age and whether altered NMDAR function is associated with the emergence of impaired executive function.…”

Section: Introductionmentioning

confidence: 99%

Impaired Attention and Synaptic Senescence of the Prefrontal Cortex Involves Redox Regulation of NMDA Receptors

2015

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Young (3-6 months) and middle-age (10 -14 months) rats were trained on the five-choice serial reaction time task. Attention and executive function deficits were apparent in middle-age animals observed as a decrease in choice accuracy, increase in omissions, and increased response latency. The behavioral differences were not due to alterations in sensorimotor function or a diminished motivational state. Electrophysiological characterization of synaptic transmission in slices from the mPFC indicated an age-related decrease in glutamatergic transmission. In particular, a robust decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in the mPFC was correlated with several measures of attention. The decrease in NMDAR function was due in part to an altered redox state as bath application of the reducing agent, dithiothreitol, increased the NMDAR component of the synaptic response to a greater extent in middle-age animals. Together with previous work indicating that redox state mediates senescent physiology in the hippocampus, the results indicate that redox changes contribute to senescent synaptic function in vulnerable brain regions involved in age-related cognitive decline.

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The ageing cortical synapse: hallmarks and implications for cognitive decline

Cited by 804 publications

References 151 publications

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

Increased axonal bouton dynamics in the aging mouse cortex

Impaired Attention and Synaptic Senescence of the Prefrontal Cortex Involves Redox Regulation of NMDA Receptors

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