d-Serine: The right or wrong isoform?

Only recently, d-amino acids have been identified in mammals. Of these, d-serine has been most extensively studied. d-Serine was found to play an important role as a neurotransmitter in the human central nervous system (CNS) by binding to the N-methyl-d-aspartate receptor (NMDAr), similar to glycine. Therefore, d-serine may well play a role in all physiological and pathological processes in which NMDArs have been implied. In this review, we discuss the findings implying an important role for d-serine in human physiology (CNS development and memory and learning) and pathology (excitotoxicity, perinatal asphyxia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, epilepsy, schizophrenia and bipolar disorder). We will debate on the relative contribution of d-serine versus glycine and conclude with clinical applications derived from these results and future directions to progress in this field. In general, adequate concentrations of d-serine are required for normal CNS development and function, while both decreased and increased concentrations can lead to CNS pathology. Therefore, d-serine appears to be the right isoform when present in the right concentrations.