Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function
Introduction
Our modern society is characterized by a constant increase in life expectancy that is driven by progress in medical care, hygiene and nutrition. On the other side of the coin, we have a concomitant increase in age-related cognitive defects, which now represent a major burden both at the medical, social and economic levels. Extensive studies of animal models of cognitive aging, notably those that examine hippocampus-related memory capacities (see Billard, 2006 for a review), indicate that memory deficits are linked to an impaired ability of the brain to drive calcium (Ca2+)-dependent plasticity of synaptic communication between neurons (Landfield and Lynch, 1977, Barnes, 1985, Landfield et al., 1986). This plasticity is a major property of the neuronal networks underlying memory formation (Barnes, 1995, Eichenbaum, 1996, Dun et al., 2008). Age-related deficits in synaptic plasticity are likely to reflect a shift in Ca2+ sources, with a weaker role for the N-methyl-d-aspartate subtype of glutamate receptors (NMDA-R) and an increased contribution of voltage-gated Ca2+ channels and intracellular stores with different kinetic properties (Kumar and Foster, 2005, Gant et al., 2006, Shankar et al., 1998, Foster, 2007, Thibault et al., 2007). However, the exact nature of the mechanisms underlying the age-related NMDA-R deficit remains open to discussion. The importance of a decrease in receptor density, as proposed previously (Adams et al., 2001, Clayton et al., 2002, Magnusson et al., 2002), was recently challenged by a study of the Lou/C/Jall strain of rats, a model of healthy aging (Alliot et al., 2002). In these animals, no obvious age-related memory impairments have yet been characterized, despite a significant loss of NMDA-R (Kollen et al., 2008). Interestingly, the impaired NMDA-R activity and synaptic plasticity that occur in aged rats of other strains (Barnes et al., 1997, Potier et al., 2000, Clayton et al., 2002) are rescued by saturating doses of d-serine, the endogenous ligand of the strychnine-insensitive glycine-binding site of the NMDA-R (Junjaud et al., 2006, Mothet et al., 2006). d-serine is synthesized from the l-isomer by direct racemization catalyzed by serine racemase, an enzyme initially localized in astrocytes but recently also found in neurons (Yasuda et al., 2001, Chumakov et al., 2002, Martineau et al., 2006, Oliet and Mothet, 2006, Wolosker, 2007, Miya et al., 2008). On the other hand, d-serine is degraded by d-amino acid oxidase (dAAO), a flavoprotein confined to astrocytes (Horiike et al., 1994, Schell et al., 1995, Urai et al., 2002).
Since it has been demonstrated that d-serine is needed for the activation of NMDA-R and the induction of NMDA-R-dependent synaptic plasticity (Yang et al., 2003), we attempted to obtain further evidence for the involvement of changes in the d-serine pathway in cognitive aging (see Junjaud et al., 2006, Mothet et al., 2006). In this study, we therefore determined and compared the expression of d-serine-related enzymes, the cerebral availability of this NMDA-R co-agonist, and synaptic plasticity in Lou/C/Jall and Wistar rats.
Section snippets
Methods
All experiments were carried out in accordance with the European Communities Council Directive (86/809/EEC) regarding the care and use of animals for experimental procedures, and were approved by the local ethics committee. The experiments were conducted with 4–6-month-old “young” (n = 14) and 25–29-month-old “aged” (n = 17) male Wistar rats purchased from Charles River (France) and 4–6-month-old “young” (n = 11) and 25–29-month-old “aged” (n = 18) Lou/C/Jall rats bred at the Complexe Scientifique des
Serine racemase expression is specifically altered in the hippocampus of aged Wistar rats
Quantitative PCR (Fig. 1A1) and western blotting (Fig. 1B1) revealed that serine racemase messenger RNA (mRNA) and protein levels were significantly decreased (−47.8%, p < 0.05, n = 5 and −25.1%, p < 0.01, n = 5 respectively) in the hippocampus of aged Wistar rats. In contrast, transcripts and protein levels of the d-serine degrading enzyme dAAO were not significantly modified (Fig. 1A1 and B1). It is worth noting that mRNA levels of the glutamate metabolizing enzyme glutamine synthetase were not
Discussion
In the CNS, the amino acid d-serine is now considered the main endogenous co-agonist for the activation of NMDA-R (Mothet et al., 2000, Mothet et al., 2006, Yang et al., 2003, Shleper et al., 2005, Panatier et al., 2006), a glutamate receptor subtype critically involved in the Ca2+-dependent synaptic plasticity underlying learning and memory (Izquierdo, 1991, Lynch, 1998, Lisman and McIntyre, 2001). By comparing animal models of intact and impaired hippocampal-related cognitive function during
Conflict of interest
The authors have no current or potential conflicts of interest to report.
Acknowledgments
We thank J. Bouvier for technical assistance, and A. Cougnon and D. Bergerot for their care of the animals. This manuscript was prepared with editorial help from Gap Junction (www.gap-junction.com).
This work was supported by the Institut National de la Santé et de la Recherche Scientifique (INSERM), and funding from the Fondation pour la Recherche Médicale (Equipe FRM to SHRO), the Agence National pour la Recherche (to SHRO), NARSAD (to SHRO) and the Institut de la Longévité et du Vieillissement
References (69)
- et al.
Tetrahydroaminoacridine and d-cycloserine stimulate acquisition of water maze spatial navigation in aged rats
Eur. J. Pharmacol.
(1998) - et al.
Pre-training blocks the improving effect of tetrahydroaminoacridine and d-cycloserine on spatial navigation performance in aged rats
Eur. J. Pharmacol.
(2000) Involvement of LTP in memory: are we “searching under the street light”?
Neuron
(1995)- et al.
Age-related decrease in the N-methyl-d-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1
Neurobiol. Aging
(1997) - et al.
d-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats
Neurobiol. Aging
(1994) - et al.
Age-related deficits as working memory load increases: relationships with growth factors
Neurobiol. Aging
(2003) - et al.
Protein kinase C activity is associated with prefrontal cortical decline in aging
Neurobiol. Aging
(2009) - et al.
Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain
Neurobiol. Aging
(2007) - et al.
Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression
Brain Res. Mol. Brain Res.
(2000) - et al.
Fat intake reverses the beneficial effects of low caloric intake on skeletal muscle mitochondrial H(2)O(2) production
Free Radic. Biol. Med.
(2005)
d-amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes
Brain Res.
Role of NMDA receptors in memory
Trends Pharmacol. Sci.
Intracellular calcium stores contribute to increased susceptibility to LTD induction during aging
Brain Res.
Memory and the brain: unexpected chemistries and a new pharmacology
Neurobiol. Learn. Mem.
Age-related changes in the protein expression of subunits of the NMDA receptor
Brain Res. Mol. Brain Res.
Frontal connections and cognitive changes in normal aging rhesus monkeys: a DTI study
Neurobiol. Aging
d-serine signalling in the brain: friend and foe
Trends Neurosci.
Age-related changes in LTP and antioxidant defenses are reversed by an alpha-lipoic acid-enriched diet
Neurobiol. Aging
Impairment in abstraction and set shifting in aged rhesus monkeys
Neurobiol. Aging
Decline in motor functions in aging is related to the loss of NMDA receptors
Brain Res.
Glia-derived d-serine controls NMDA receptor activity and synaptic memory
Cell
Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats
Neuroscience
NMDA receptor activation in the aged rat hippocampus
Exp. Gerontol.
Gene expression of d-amino acid oxidase in cultured rat astrocytes: regional and cell type specific expression
Neurosci. Lett.
Age-related decline in water maze learning and memory in rats: strain differences
Neurobiol. Aging
Immunohistochemical evidences for localization and production of d-serine in some neurons in the rat brain
Neurosci. Lett.
Hippocampal dependent learning ability correlates with N-methyl-d-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats
J. Comp. Neurol.
The LOU/c/jall rat as an animal model of healthy aging?
J. Gerontol. A Biol. Sci. Med. Sci.
An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses
Behav. Neurosci.
Targeted disruption of serine racemase affects glutamatergic neurotransmission and behavior
Mol. Psychiatry
Ageing, hippocampal synaptic activity and magnesium
Magnes. Res.
d-serine signalling as a prominent determinant of neuronal-glial dialogue in the healthy and diseased brain
J. Cell Mol. Med.
Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia
Proc. Natl. Acad. Sci. U.S.A.
A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat
J. Neurosci.
Cited by (73)
Hydrogen sulfide-induced post-translational modification as a potential drug target
2023, Genes and DiseasesTargeting redox-altered plasticity to reactivate synaptic function: A novel therapeutic strategy for cognitive disorder
2021, Acta Pharmaceutica Sinica BAging modifies concentration and metabolism of amino acids and associated receptor functionality in the brain
2021, Factors Affecting Neurological Aging: Genetics, Neurology, Behavior, and DietThe impact of aged microglia on d-serine-regulated glutamatergic transmission
2021, Factors Affecting Neurological Aging: Genetics, Neurology, Behavior, and DietD-serine in physiological and pathological brain aging
2021, Biochimica et Biophysica Acta - Proteins and ProteomicsCitation Excerpt :The decrease in SR expression and d-serine production possibly results from the development of the oxidative stress (OS) that normally occurs with aging [49–52]. Indeed, both deficits do not occur in the LOU/C rat [36], a model of successful aging characterized by a high degree of resistance to OS [53–56]. They are also prevented in aged animals receiving a long-term treatment with the reducing compound N-acetyl-cysteine in which the extent of OS is minimized [57].
Sp4 controls constitutive expression of neuronal serine racemase and NF-E2-related factor-2 mediates its induction by valproic acid
2020, Biochimica et Biophysica Acta - Gene Regulatory MechanismsCitation Excerpt :Serine racemase (SR) is a pyridoxal 5′-phosphate and calcium-dependent allosteric enzyme which catalyzes l-serine to d-serine, an endogenous co-agonist of N-methyl-d-aspartate receptor (NMDAR) [1,2]. By acting upon GluN1 subunit of NMDAR, d-serine participates in NMDAR-mediated physiologica process such as neurotransmission, synaptic plasticity, and granule cell migration during the development of the cerebellum [3–5]. d-serine level is balanced by SR synthesis and D-amino acid oxidase (DAAO) degradation.