Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function

Abstract To gain insight into the contribution of d -serine to impaired cognitive aging, we compared the metabolic pathway and content of the amino acid as well as d -serine-dependent synaptic transmission and plasticity in the hippocampus of young and old rats of the Wistar and Lou/C/Jall strains....

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Published in:	Neurobiology of aging Vol. 32; no. 8; pp. 1495 - 1504
Main Authors:	Turpin, F.R, Potier, B, Dulong, J.R, Sinet, P.-M, Alliot, J, Oliet, S.H.R, Dutar, P, Epelbaum, J, Mothet, J.-P, Billard, J.-M
Format:	Journal Article
Language:	English
Published:	London Elsevier Inc 01-08-2011 Elsevier
Subjects:	Aging - genetics Aging - physiology Animals Biological and medical sciences Cognition Disorders - enzymology Cognition Disorders - genetics d-serine Development. Senescence. Regeneration. Transplantation Fundamental and applied biological sciences. Psychology Gene Expression Regulation, Enzymologic Hippocampus Hippocampus - enzymology Hippocampus - physiology Internal Medicine Life Sciences Male Memory Memory Disorders - enzymology Memory Disorders - genetics Memory Disorders - physiopathology Neurology Neurons and Cognition NMDA receptor Racemases and Epimerases - antagonists & inhibitors Racemases and Epimerases - biosynthesis Racemases and Epimerases - genetics Rats Rats, Wistar Signal Transduction - genetics Signal Transduction - physiology Synaptic plasticity Vertebrates: nervous system and sense organs M-MLV Memory d-APV N-methyl- d-aspartate-receptor LTP mRNA d-amino acid oxidase fEPSP messenger RNA presynaptic fiber volley reactive oxygen species Synaptic plasticity Moloney Murine Leukemia Virus PFV field excitatory postsynaptic potentials dAAO d-serine artificial cerebrospinal fluid 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide d-2-amino-5-phosphonovalerate NMDA-R ROS aCSF NMDA receptor Hippocampus long-term potentiation NBQX Senescence D-serine Serine Central nervous system Glutamate receptor Cognition Age Encephalon
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Summary:	Abstract To gain insight into the contribution of d -serine to impaired cognitive aging, we compared the metabolic pathway and content of the amino acid as well as d -serine-dependent synaptic transmission and plasticity in the hippocampus of young and old rats of the Wistar and Lou/C/Jall strains. Wistar rats display cognitive impairments with aging that are not found in the latter strain, which is therefore considered a model of healthy aging. Both mRNA and protein levels of serine racemase, the d -serine synthesizing enzyme, were decreased in the hippocampus but not in the cerebral cortex or cerebellum of aged Wistar rats, whereas the expression of d -amino acid oxidase, which degrades the amino acid, was not affected. Consequently, hippocampal levels of endogenous d -serine were significantly lower. In contrast, serine racemase expression and d -serine levels were not altered in the hippocampus of aged Lou/C/Jall rats. Ex vivo electrophysiological recordings in hippocampal slices showed a marked reduction in N -methyl- d -aspartate-receptor (NMDA-R)-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) in the CA1 area of aged Wistar rats, which were restored by exogenous d -serine. In contrast, NMDA-R activation, LTP induction and responses to d -serine were not altered in aged Lou/C/Jall rats. These results further strengthen the notion that the serine racemase-dependent pathway is a prime target of hippocampus-dependent cognitive deficits with aging. Understanding the processes that specifically affect serine racemase during aging could thus provide key insights into the treatment of memory deficits in the elderly.
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ISSN:	0197-4580 1558-1497
DOI:	10.1016/j.neurobiolaging.2009.09.001