Most naturally occuring amino acids in animals are of the L stereoisomerism, but D-serine is an amino acid that does have biological activity. It is known to activate NMDA receptors and induce NDMA receptor-dependent synaptic plasticity. And, there is evidence that deficiencies in D-serine are involved in the decline in hippocampus-dependent memory that occurs during aging.
Serine racemase is the enzyme that converts the naturally occuring L-serine to D-serine. Turpin et al looked at the mRNA and protein levels of D-serine in young and old Wistar rats as well as young and old Lou/C/Jall rats, which represent a model of aging without memory decline. D-serine levels were significantly reduced only in the hippocampus of aged Wistar rats as compared to young ones, −47.8% for mRNA levels and −25.1% for protein levels. When the researchers induced isolated NMDA receptor based field excitatory postsynaptic potentials on transverse hippocampal slices in Wistar rats, the recording was weaker in old animals than young ones. This difference between old and young was not apparent in the recordings from Lou/C/Jall rats. Crucially, when exogenous D-serine was added to the cerebrospinal fluid of Wistar rats, the age-related decrease in isolated NMDA receptor mediated synaptic potentials was rescued and there were no longer any signifcant difference between young and old rats. This strongly suggests that diminished D-serine can be responsible for lowered activity by NMDA receptors in the hippocampus.
Interestingly, the authors note that Lou/C/Jall rats have a reduced oxidative metabolism and less ROS production as compared to other strains (i.e., Wistar), don’t show any age-dependent reductions in the expression of serine racemase, and are generally a model for healthy aging without cognitive decline. Thus, the serine racemase gene may be a common and/or prototypical target of DNA-based oxidative damage in the aging brain.
Turpin FR, et al. 2009 Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function. Neurobiology of Aging, Article in Press. doi:10.1016/j.neurobiolaging.2009.09.001.