D-Serine (DSR) is an endogenous amino acid involved in glia-synapse interactions that has unique neurotransmitter characteristics. DSR acts as obligatory coagonist at the glycine site associated with the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) and has a cardinal modulatory role in major NMDAR-dependent processes including NMDAR-mediated neurotransmission, neurotoxicity, synaptic plasticity, and cell migration. Since either over- or underfunction of NMDARs may be involved in the pathophysiology of neuropsychiatric disorders; the pharmacological manipulation of DSR signaling represents a major drug development target. A first generation of proof-of-concept animal and clinical studies suggest beneficial DSR effects in treatment-refractory schizophrenia, movement, depression, and anxiety disorders and for the improvement of cognitive performance. A related developing pharmacological strategy is the indirect modification of DSR synaptic levels by use of compounds that alter the function of main enzymes responsible for DSR production and degradation. Accumulating data indicate that, during the next decade, we will witness important advances in the understanding of DSR role that will further contribute to elucidating the causes of neuropsychiatric disorders and will be instrumental in the development of innovative treatments. 1. Introduction Although the enzyme D-amino-acid oxidase (DAAO) has been identified in higher organisms in 1935 [1], historically, D-amino acids were thought to be absent in mammalian tissue. This dogma was revolutionized at the beginning of 1990’s when it was found that abundant quantities of free D-serine (DSR) occur in the mammalian brain, at concentrations comparable with those of classical neurotransmitters and higher than those of most essential amino acids [2, 3]. Presently, DSR is considered the most biologically active D-amino acid described in mammalian systems [4]. Phylogenetically, its concentrations appear to be extremely low in the brains of fish, amphibians, and birds, suggesting that endogenous DSR is specifically maintained at high levels in the mammalian brain among vertebrates [5]. In the late 1990s, it was demonstrated that DSR is an obligatory endogenous coagonist of the N-methyl-D-aspartate receptor (NMDAR), functioning in vivo as a specific and potent full agonist at the NMDAR-associated glycine (GLY) modulatory site (GMS). The NMDAR subtype of glutamate (GLU) receptors is widely expressed in the central nervous system (CNS) and has a cardinal role in activity-dependent changes in synaptic
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