d-Serine in the aging hippocampus

• d-Serine-mediated functional plasticity is impaired in the aging hippocampus.
• Reduced d-serine synthesis underlies the age-related functional deficits.
• The d-serine producing enzyme is targeted by the age-associated oxidative stress.
• Supplementation with d-serine rescues deficits in CA1 area but not dentate gyrus.

Experimental evidences now indicate that memory formation relies on the capacity of neuronal networks to manage long-term changes in synaptic communication. This property is driven by N-methyl-d-aspartate receptors (NMDAR), which requires the binding of glutamate but also the presence of the co-agonist d-serine at the glycine site. Defective memory function and impaired brain synaptic plasticity observed in aging are rescued by partial agonist acting at this site suggesting that this gating process is targeted to induce age-related cognitive defects. This review aims at compelling recent studies characterizing the role of d-serine in changes in functional plasticity that occur in the aging hippocampus since deficits are rescued by d-serine supplementation. The impaired efficacy of endogenous d-serine is not due to changes in the affinity to glycine-binding site but to a decrease in tissue levels of the amino acid resulting from a weaker expression of the producing enzyme serine racemase (SR). Interestingly, neither SR expression, d-serine levels, nor NMDAR activation is affected in aged LOU/C rats, a model of healthy aging in which memory deficits do not occur. These old animals do not develop oxidative stress suggesting that the d-serine-related pathway could be targeted by the age-related accumulation of reactive oxygen species. Accordingly, senescent rats chronically treated with the reducing agent N-acetyl-cysteine to prevent oxidative damage, show intact NMDAR activation linked to preserved d-serine levels and SR expression.These results point to a significant role of d-serine in age-related functional alterations underlying hippocampus-dependent memory deficits, at least within the CA1 area since the amino acid does not appear as critical in changes affecting the dentate gyrus.

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