New insights on the influence of free D-aspartate metabolism in the mammalian brain during prenatal and postnatal life

Free D-aspartate is abundant in the mammalian embryonic brain. However, following the postnatal onset of the catabolic D-aspartate oxidase (DDO) activity, cerebral D-aspartate levels drastically decrease, remaining constantly low throughout life. D-Aspartate stimulates both glutamatergic NMDA receptors (NMDARs) and metabotropic Glu5 receptors. In rodents, short-term D-aspartate exposure increases spine density and synaptic plasticity, and improves cognition. Conversely, persistently high D-Asp levels produce NMDAR-dependent neurotoxic effects, leading to precocious neuroinflammation and cell death. These pieces of evidence highlight the dichotomous impact of D-aspartate signaling on NMDAR-dependent processes and, in turn, unveil a neuroprotective role for DDO in preventing the detrimental effects of excessive D-aspartate stimulation during aging. Here, we will focus on the in vivo influence of altered D-aspartate metabolism on the modulation of glutamatergic functions and its involvement in translational studies. Finally, preliminary data on the role of embryonic D-aspartate in the mouse brain will also be reviewed.