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

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.

Deficit of NMDA receptor activation in CA1 hippocampal area of aged rats is rescued by D-cycloserine.

Activation of the glycine modulatory site of the N-methyl-D-aspartate glutamate receptor (NMDAR) may reduce cognitive impairments associated with normal ageing. In order to test this hypothesis, we assessed the effects of the partial agonist D-cycloserine (DCS) on cellular activities involved in memory formation. This was performed in CA1 cellular networks of adult and aged Sprague-Dawley rat hippocampal slices using extracellular field excitatory postsynaptic potential recordings. Synaptic potentials specifically mediated by NMDAR were significantly reduced in aged animals. DCS increased the magnitude of these responses in both adult and old rats but this effect was significantly higher in the latter, thus reversing the age-related decrease in NMDAR synaptic potentials. NMDAR-mediated theta burst long-term potentiation (TBS-LTP) as well as long-term depression (LTD) of synaptic transmission, prominent models for the cellular basis of learning and memory, were also weakened in aged animals. Age-related alterations of both forms of synaptic plasticity were rescued by DCS. In addition, the DCS-induced decrease in basal fast glutamatergic neurotransmission involving the activation of inhibitory glycinergic receptors, previously reported in young rats (Rouaud & Billard, 2003), was severely attenuated in aged animals. In summary, our results indicate that the facilitation of NMDAR activation through its glycine-binding site rescues the age-related deficit of cellular mechanisms of learning and memory. Such physiological evidences suggest that this modulation site of NMDAR represents an important target to alleviate cognitive deficits associated with normal ageing.

A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory.

Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging, the content of D-serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D-serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D-serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.

Age-related effects of the neuromodulator D-serine on neurotransmission and synaptic potentiation in the CA1 hippocampal area of the rat.

The effects of the co-agonist of the N-methyl-D-aspartate receptor (NMDAr) D-serine on glutamatergic neurotransmission and synaptic potentiation were studied in the CA1 hippocampal field of young (3-5 months old) and aged (25-27 months old) Sprague-Dawley rats using ex vivo extracellular electrophysiological recording techniques. Exogenous d-serine depressed fast neurotransmission mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate subtype of glutamate receptors in young but not in aged rats by acting on inhibitory glycinergic interneurons. In contrast, D-serine dose-dependently enhanced NMDAr-mediated synaptic responses in both groups of animals, but with a larger magnitude in aged rats, thus preventing the age-related decrease in NMDAr activation. D-serine also increased the magnitude of long-term potentiation in aged but not in young rats. Finally, D-serine levels were dramatically reduced in hippocampal tissues of aged rats. Taken together, these results indicate a weaker activation of the NMDAr glycine modulatory site by endogenous D-serine in aged animals, which accounts for a reduced NMDAr contribution to synaptic plasticity in ageing.

D-cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices.

1. The glycine-binding site of the glutamatergic N-methyl-d-aspartate receptor subtype (NMDAr) has been proposed as a putative target for treating cognitive impairments in neurodegenerative disorders and schizophrenia. Although behavioural evidence has been accumulated showing that the partial agonist d-cycloserine (DCS) facilitated learning and memory, physiological mechanisms of the drug still remained to be characterized. In the present study, we have investigated the effects of DCS on glutamatergic neurotransmission and synaptic plasticity in CA1 region of rat hippocampal slices, using extracellular field excitatory postsynaptic potentials. 2. We showed that DCS facilitated NMDAr-mediated synaptic potentials. In addition, we found that the magnitude of NMDAr-dependent long-term depression was significantly enhanced by the agonist, while the threshold for the induction of lasting potentiations was lowered. 3. We found that DCS decreased neurotransmission mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate subtypes of glutamate receptors. This inhibition was not prevented by the gamma-aminobutyric acid GABAA antagonist bicuculline, but was antagonized by the glycine antagonist strychnine. 4. These results, therefore, show opposite effects of DCS on NMDA and non-NMDA synaptic responses within the hippocampus. They also demonstrate that DCS facilitates long-term synaptic plasticity that may support the DCS-induced enhanced cognitive performances.