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

Centre de Psychiatrie et Neurosciences, INSERM, U894, Faculté de Médecine, Université Paris Descartes Paris, France.
Frontiers in Aging Neuroscience (Impact Factor: 4). 02/2010; 2:1. DOI: 10.3389/neuro.24.001.2010
Source: PubMed


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.

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Available from: Fabrice Turpin
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    • "In addition, saturating NMDA-R co-agonist binding sites with exogenous glycine does not rescue the impaired LTP displayed by aged animals. Importantly, our results also indicate that D-serine does not play a major role in these aged-related deficits, since neither impaired LTP nor reduced NMDA-R activation is reversed by providing the D-amino acid to tissues, in striking contrast to what has been found in the CA1 area (Potier et al. 2010). These results therefore indicate that the putative consequences of age-related changes in the activation of NMDA-R co-agonist binding sites are minimal in the dentate gyrus, compared to the importance of these alterations in CA1 neuronal networks. "
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    ABSTRACT: Age-related memory deficits have recently been associated with the impaired expression of D-serine-dependent synaptic plasticity in neuronal networks of the hippocampal CA1 area. However, whether such functional alterations are common to the entire hippocampus during aging remains unknown. Here, we found that D-serine was also required for the induction of N-methyl-D-aspartate receptor (NMDA-R)-dependent long-term potentiation (LTP) at perforant path-granule cell synapses of the dentate gyrus. LTP as well as isolated NMDA-R synaptic potentials were impaired in slices from aged rats, but in contrast to the CA1, this defect was not reversed by exogenous D-serine. The lower activation of the glycine-binding site by the endogenous co-agonist does not therefore appear to be a critical mechanism underlying age-related deficits in NMDA-R activation in the dentate gyrus. Instead, our data highlight the role of changes in presynaptic inputs as illustrated by the weaker responsiveness of afferent glutamatergic fibers, as well as changes in postsynaptic NMDA-R density. Thus, our study indicates that although NMDA-R-dependent mechanisms driving synaptic plasticity are quite similar between hippocampal circuits, they show regional differences in their susceptibility to aging, which could hamper the development of effective therapeutic strategies aimed at reducing cognitive aging.
    Full-text · Article · Oct 2014 · Journal of the American Aging Association
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    • "Abnormal levels of D-serine have been reported in aging (Potier et al., 2010; Turpin et al., 2011; Haxaire et al., 2012; Billard, 2013), Alzheimer’s disease (Wu et al., 2004) and amyotrophic lateral sclerosis (ALS; Sasabe et al., 2012; Paul and de Belleroche, 2014). Moreover, D-serine has emerged as an influential player in the context of psychiatric diseases such as schizophrenia and depression. "
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    ABSTRACT: Cocaine addiction is characterized by compulsive drug use despite adverse consequences and high rate of relapse during periods of abstinence. Increasing consensus suggests that addiction to drugs of abuse usurps learning and memory mechanisms normally related to natural rewards, ultimately producing long-lasting neuroadaptations in the mesocorticolimbic system. This system, formed in part by the ventral tegmental area and nucleus accumbens (NAc), has a central role in the development and expression of addictive behaviors. In addition to a broad spectrum of changes that affect morphology and function of NAc excitatory circuits in cocaine-treated animals, impaired N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity is a typical feature. D-serine, a D-amino acid that has been found at high levels in mammalian brain, binds with high affinity the co-agonist site of NMDAR and mediates, along with glutamate, several important processes including synaptic plasticity. Here we review recent literature focusing on cocaine-induced impairment in synaptic plasticity mechanisms in the NAc and on the fundamental role of D-serine as co-agonist of NMDAR in functional and dysfunctional synaptic plasticity within this nucleus. The emerging picture is that reduced D-serine levels play a crucial role in synaptic plasticity relevant to cocaine addiction. This finding opens new perspectives for therapeutic approaches to treat this addictive state.
    Full-text · Article · Jul 2014 · Frontiers in Synaptic Neuroscience
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    • "Because memory formation is now viewed as being closely dependent on the capacity of the brain to regulate long-lasting changes in neuronal communication (Martin et al., 2000; Lisman & McIntyre, 2001), age-related deficits in learning and memory could occur in parallel with the impairment of functional plasticity at central synapses. Experimental data confirm this assumption, because the expression of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission, is altered in the brain of memory-deficient aged animals (Clayton et al., 2002; Foster, 2006; Potier et al., 2010). The N-methyl-D-aspartate subtype of glutamate receptors (NMDA-R) is known to play a major role in the induction of synaptic plasticity as well as in the acquisition of memory traces (Morris et al., 1990; Izquierdo, 1991). "
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    ABSTRACT: Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl- d-aspartate receptor (NMDA-R) by its co-agonist d-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long-term dietary supplementation with L-NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA-R-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous d-serine. Chronic treatment with L-NAC, but not acute application of the reducing agent, restored potent d-serine-dependent NMDA-R activation and LTP induction in aged rats. In addition, it is also revealed that the age-related decrease in d-serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA-R activation by the amino acid, was rescued by long-term dietary treatment with L-NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA-R activation through the d-serine-dependent pathway.
    Full-text · Article · Jan 2012 · Aging cell
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