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. 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.

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.