Increased d-aspartate brain content rescues hippocampal age-related synaptic plasticity deterioration of mice

Until recently, free d-amino acids were thought to be involved only in bacterial physiology. Nevertheless, today there is evidence that d-serine, by acting as co-agonist at NMDARs, plays a role in controlling neuronal functions in mammals. Besides d-serine, another d-amino acid, d-aspartate (d-Asp), is found in the mammalian brain with a temporal gradient of occurrence: high in embryo and low in adult. In this study, we demonstrate that d-Asp acts as an endogenous NMDAR agonist, since it triggers currents via interaction with each of NR2A-D receptor subunits. According to its pharmacological features, we showed that oral administration of d-Asp strongly enhances NMDAR-dependent LTP in adulthood and, in turn, completely rescues the synaptic plasticity decay observed in the hippocampus of aged animals. Therefore, our findings suggest a tantalizing hypothesis for which this in-embryo-occurring d-amino acid, when “forced” over its physiological content, may disclose plasticity windows inside which it counteracts the age-related reduction of NMDAR signaling.