Impaired neuroplasticity in the aging brain : Contribution of the D-serine pathway.
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Université Paris Descartes, Paris F-75014, France.
In the general decline that gradually develops with age, learning and memory deficits are frequent features. Studies in animal models of aging have confirmed the occurrence of a cognitive decline with age and shown that memory deficits are associated with an impaired neuroplasticity in the aging brain, including the long-term potentiation and depression (LTP and LTD) forms of synaptic plasticity. In cerebral areas involved in memory processing such as the hippocampus, activation of N-Methyl-d-Aspartate receptors (NMDA-R) is required for the expression of synaptic plasticity. In addition to glutamate, the binding of the endogenous co-agonist d-serine at the strychnine insensitive glycine site is needed for NMDA-R activation. Our recent findings indicate that age-related deficits of synaptic plasticity in the rat hippocampus correlate with changes in d-serine availability. Endogenous d-serine levels are significantly decreased in hippocampal tissues of aged rats indicating that the metabolism of the amino acid is altered by age. Accordingly, the expression of serine racemase (SR), the synthesizing enzyme of d-serine, is lowered whereas that the degrading enzyme, d-amino acid oxidase remains unaffected. On the other hand, addition of exogenous d-serine in hippocampal slices prevents the age-related deficits of LTP and LTD and of isolated NMDA-R-dependent synaptic potentials.
Studies in the LOU/C/Jall rat, a model of healthy aging displaying increased lifespan, show that D-serine availability is preserved in this strain across aging. Interestingly, LTP and LTD expression remain unaffected in these aged animals, which also display memory capacities similar to those of young subjects.
All together, these results raise a critical role of the d-serine-dependent pathway in functional alterations of the brain underlying impaired cognitive aging. These researches would therefore provide key insights in the search of new therapeutic strategies aimed at reducing memory deficits in the elderly.