Alterations in D-amino Acid Metabolism in Psychiatric and Neurological Disorders

Dear Colleagues,

All amino acids, except glycine, have a chiral carbon center that allows for the formation of two stereoisomers that are mirror images of each other. However, despite the potential to exist as both left-handed (L) and right-handed (D) forms, animal organisms exclusively use L-amino acids as building blocks of proteins and intermediates of biochemical processes. In this context, the free D-amino acids identified for the first time between the 1980s and the 1990s in biological tissues of mammals, including humans, were initially considered a by-product derived from the diet and/or the intestinal bacterial flora. However, the recent discovery of enzymes involved in free D-amino acids biosynthesis, along with the long-established existence of enzymes responsible for selective D-amino acid degradation, have led to the hypothesis that these “unusual” molecules might have a role in the biology of mammals. To date, several D-amino acids have been identified in the mammalian brain and peripheral organs. Among them, D-serine and D-aspartate have been reported to occur in larger amounts and to emerge in a time- and tissue-dependent manner. In the central nervous system, D-serine and D-aspartate bind to the N-methyl D-aspartate (NMDA) subtype of glutamate receptors, the former as a co-agonist at the glycine binding site, the latter as a direct agonist at the glutamate binding site. In the light of their respective pharmacological abilities, different studies in animal models and humans have shown that these D-amino acids are able to modulate different NMDA receptor-dependent processes, including synaptic plasticity, brain development and cognition. It is well known that NMDA receptors are also implicated in brain aging, and their dysfunctional activity is relevant to the etiology and pathophysiology of a wide range of psychiatric and neurological disorders, including schizophrenia, autism, depression, addiction, amyotrophic lateral sclerosis, multiple sclerosis and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Given their neuromodulatory influence on NMDA receptors, different studies have recently evaluated the involvement of D-serine and D-aspartate in some of the abovementioned disorders, finding a dysregulated metabolism of these molecules and hypothesizing, in some instances, a potential role as biomarkers or therapeutic agents. These issues, however, are still matter of debate within the scientific community.

Based on this bulk of evidence and on the still unresolved questions, in this Special Issue, we invite scientists to submit original research articles and review articles exploring the role of D-serine, D-aspartate and possibly other D-amino acids in the neurobiology and in neuropathology of psychiatric and neurological disorders.

Prof. Dr. Alessandro Usiello
Dr. Francesco Errico
Guest Editors

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• neurological disorders
• psychiatric disorders
• NMDA receptors
• D-aspartate
• D-serine