New evidence on the role of d‐aspartate metabolism in regulating brain and endocrine system physiology: From preclinical observations to clinical applications

The endogenous amino acids serine and aspartate occur at high concentrations in free D‐ form in mammalian organs, including the central nervous system and endocrine glands. D‐serine (D‐Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D‐Ser plays a functional role by acting as an endogenous coagonist at N‐methyl‐ D‐aspartate receptors (NMDARs). Less is known about the role of free D‐aspartate (D‐Asp) in mammals. Notably, D‐Asp has a specific temporal pattern of occurrence. In fact, free D‐Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D‐Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D‐Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D‐Asp on NMDAR‐mediated responses. Herein we review the physiological function of free D‐Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.