Fig. 1: D-serine circuits, sympotom clusters, and the ‘serine shuttle'.

a Diagram illustrating the human and rodent forebrain regions expressing high levels of serine racemase that are implicated in the major post-traumatic stress disorder symptom clusters. b Schematic representation of the serine shuttle in astrocytes and neurons. Glucose is transported from the blood into astrocytes by glucose transporter-1. Most brain l-serine is synthesized de novo from the glycolytic intermediate 3-phosphoglycerate, with phosphoglycerate 3-dehydrogenase being the committed step in astrocytic l-serine biosynthesis. l-serine is released from astrocytes by the alanine/serine/cysteine/threonine transporter-1 and is then taken up into neurons via currently unidentified transporter(s), where it is converted to d-serine by the enzyme serine racemase. Serine racemase is strongly inhibited by glycine, which competes for binding with l-serine. Serine racemase and d-serine are concentrated in dendrites and dendritic spines of glutamatergic and GABAergic neurons. d-serine is released from neurons, in part, by the alanine-serine-cysteine-1 transporter, where it binds to the glycine modulatory site on synaptic N-methyl-d-aspartate receptors. Glycine also regulates d-serine metabolism by affecting the efficiency of d-serine transport, as it is a high-affinity substrate of the alanine-serine-cysteine-1 transporter and can enhance the release of d-serine by amino acid hetero-exchange. d-serine can be eliminated from the synaptic space by either reuptake into astrocytes where it is catabolized by d-amino acid oxidase or via neuronal serine racemase. Asc-1 alanine-serine-cysteine-1, Slc7a10 solute carrier family 7 member 10, ASCT-1 alanine/serine/cysteine/threonine transporter-1 (Slc1a4; solute carrier Family 1 member 4), DAO d-amino acid oxidase, GLUT1 glucose transporter-1, GlyT-1 glycine transporter-1, mPFC medial prefrontal cortex, NMDAR N-methyl-d-aspartate receptor, PHGDH phosphoglycerate 3-dehydrogenase, PSD postsynaptic density, SHMT serine hydroxymethyltransferase, SR serine racemase, Some clipart in this figure were downloaded from https://smart.servier.com.