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Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging.

Potier B, Turpin FR, Sinet PM, Rouaud E, Mothet JP, Videau C, Epelbaum J, Dutar P, Billard JM - Front Aging Neurosci (2010)

Bottom Line: Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation.Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid.On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging.

View Article: PubMed Central - PubMed

Affiliation: Centre de Psychiatrie et Neurosciences, INSERM, U894, Faculté de Médecine, Université Paris Descartes Paris, France.

ABSTRACT
An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the d-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly.

No MeSH data available.


Related in: MedlinePlus

Spatial learning and hippocampal synaptic plasticity are impaired in aged rats. (A, left) Comparison of the distance swum before escaping onto the hidden platform over 6 days of training in adult and aged rats (##p < 0.01, repeated measures ANOVA). (A, right) Comparison of time spent by rats swimming through the different quadrants, including quadrant 4, where the platform was situated during place learning, registered over a 90-s probe trial (#p < 0.05, unpaired t-test). (B, left) Time-course of LTP induction in adult and aged rats by HFS (arrow). (B, right) Comparison of mean LTP magnitude (±SEM) calculated for the last 15 min of recording. (C, left) Time course of depotentiation of previously HFS-potentiated synaptic responses induced in adult and aged rats by LFS. (C, right) Comparison of depotentiation magnitude (±SEM) calculated for the last 15 min of recording. (D) Illustration of results obtained with TBS protocols. (#p < 0.05, ##p < 0.01, unpaired t-test).
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Figure 1: Spatial learning and hippocampal synaptic plasticity are impaired in aged rats. (A, left) Comparison of the distance swum before escaping onto the hidden platform over 6 days of training in adult and aged rats (##p < 0.01, repeated measures ANOVA). (A, right) Comparison of time spent by rats swimming through the different quadrants, including quadrant 4, where the platform was situated during place learning, registered over a 90-s probe trial (#p < 0.05, unpaired t-test). (B, left) Time-course of LTP induction in adult and aged rats by HFS (arrow). (B, right) Comparison of mean LTP magnitude (±SEM) calculated for the last 15 min of recording. (C, left) Time course of depotentiation of previously HFS-potentiated synaptic responses induced in adult and aged rats by LFS. (C, right) Comparison of depotentiation magnitude (±SEM) calculated for the last 15 min of recording. (D) Illustration of results obtained with TBS protocols. (#p < 0.05, ##p < 0.01, unpaired t-test).

Mentions: Spatial learning was explored in adults (n = 10) and aged animals (n = 12) using different versions of the Morris water maze protocol. As illustrated in Figure 1A (left), the distance swum to find the platform differed greatly between groups (p < 0.0001) and a significant interaction between group and time was observed, since aged rats swam longer distances before reaching the hidden platform in the “place” version of the task (interaction of distance × group/age, p < 0.01). When each group was examined separately, adult rats efficiently learned the position of the platform across trials, as demonstrated by a significant decrease in the distance swum before finding the platform in each subsequent trial (p < 0.005), whereas aged rats did not (p = 0.3). When animals were tested 24 h after the end of the learning sessions, adult rats spent more time swimming in the quadrant in which the platform was located during place learning, whereas aged ones did not (Figure 1A, right). In contrast, the two groups of animals did not differ in swim speed during place learning (15.3 ± 0.9 cm/s in adults vs. 12.4 ± 1.1 cm/s in aged animals) and in distance swum or time to escape onto a visible platform in the cued version of the maze (not shown). These results indicate that aged rats are significantly impaired with respect to spatial learning and that these deficits are independent of sensory and/or motor dysfunctions.


Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging.

Potier B, Turpin FR, Sinet PM, Rouaud E, Mothet JP, Videau C, Epelbaum J, Dutar P, Billard JM - Front Aging Neurosci (2010)

Spatial learning and hippocampal synaptic plasticity are impaired in aged rats. (A, left) Comparison of the distance swum before escaping onto the hidden platform over 6 days of training in adult and aged rats (##p < 0.01, repeated measures ANOVA). (A, right) Comparison of time spent by rats swimming through the different quadrants, including quadrant 4, where the platform was situated during place learning, registered over a 90-s probe trial (#p < 0.05, unpaired t-test). (B, left) Time-course of LTP induction in adult and aged rats by HFS (arrow). (B, right) Comparison of mean LTP magnitude (±SEM) calculated for the last 15 min of recording. (C, left) Time course of depotentiation of previously HFS-potentiated synaptic responses induced in adult and aged rats by LFS. (C, right) Comparison of depotentiation magnitude (±SEM) calculated for the last 15 min of recording. (D) Illustration of results obtained with TBS protocols. (#p < 0.05, ##p < 0.01, unpaired t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2874399&req=5

Figure 1: Spatial learning and hippocampal synaptic plasticity are impaired in aged rats. (A, left) Comparison of the distance swum before escaping onto the hidden platform over 6 days of training in adult and aged rats (##p < 0.01, repeated measures ANOVA). (A, right) Comparison of time spent by rats swimming through the different quadrants, including quadrant 4, where the platform was situated during place learning, registered over a 90-s probe trial (#p < 0.05, unpaired t-test). (B, left) Time-course of LTP induction in adult and aged rats by HFS (arrow). (B, right) Comparison of mean LTP magnitude (±SEM) calculated for the last 15 min of recording. (C, left) Time course of depotentiation of previously HFS-potentiated synaptic responses induced in adult and aged rats by LFS. (C, right) Comparison of depotentiation magnitude (±SEM) calculated for the last 15 min of recording. (D) Illustration of results obtained with TBS protocols. (#p < 0.05, ##p < 0.01, unpaired t-test).
Mentions: Spatial learning was explored in adults (n = 10) and aged animals (n = 12) using different versions of the Morris water maze protocol. As illustrated in Figure 1A (left), the distance swum to find the platform differed greatly between groups (p < 0.0001) and a significant interaction between group and time was observed, since aged rats swam longer distances before reaching the hidden platform in the “place” version of the task (interaction of distance × group/age, p < 0.01). When each group was examined separately, adult rats efficiently learned the position of the platform across trials, as demonstrated by a significant decrease in the distance swum before finding the platform in each subsequent trial (p < 0.005), whereas aged rats did not (p = 0.3). When animals were tested 24 h after the end of the learning sessions, adult rats spent more time swimming in the quadrant in which the platform was located during place learning, whereas aged ones did not (Figure 1A, right). In contrast, the two groups of animals did not differ in swim speed during place learning (15.3 ± 0.9 cm/s in adults vs. 12.4 ± 1.1 cm/s in aged animals) and in distance swum or time to escape onto a visible platform in the cued version of the maze (not shown). These results indicate that aged rats are significantly impaired with respect to spatial learning and that these deficits are independent of sensory and/or motor dysfunctions.

Bottom Line: Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation.Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid.On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging.

View Article: PubMed Central - PubMed

Affiliation: Centre de Psychiatrie et Neurosciences, INSERM, U894, Faculté de Médecine, Université Paris Descartes Paris, France.

ABSTRACT
An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the d-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly.

No MeSH data available.


Related in: MedlinePlus