Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function.
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.
Centre de Psychiatrie et Neurosciences, INSERM, UMR 894, Université Paris Descartes, Faculté de Médecine René Descartes, Paris, F-75014, France. fabrice.turpin@inserm.fr
F R
FR
Turpin
B
B
Potier
J R
JR
Dulong
P-M
PM
Sinet
J
J
Alliot
S H R
SH
Oliet
P
P
Dutar
J
J
Epelbaum
J-P
JP
Mothet
J-M
JM
Billard
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003072:Cognition Disorders / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology*; D008297:Male; D008569:Memory Disorders / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000099300:Serine Racemase
D019998:Racemases and Epimerases; D000099300:Serine Racemase