Metabolism and Physiological functions of endogenous D-serine

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To obtain an insight into physiological and pathophysiological role of endogenous D-serine in higher brain functions, we have investigated the metabolism of D-serine in the rat and human brain tissues. Substantial concentration of D-serine has been detected in the extracellular fluid of the frontal cortex and striatum of the rat by an in vivo microdialysis technique. Neither calcium ion-free condition nor perfusion of tetrodotoxin reduced extracellular D-serine content in the frontal cortex and a depolarization agent, veratrin, caused an increase in the extracellular release of glutamate, but not D-serine. These data suggest that extracellular D-serine could be liberated from glial cells. [3H]D-Serine was found to be taken up into the cortical and cerebellar P2 franction and the C6 glioma cells in a temperature-and sodium-dependent and saturable manner, indicating the presence a transport system for D-serine. In addition to the glycine modulatory site of the NMDA receptor at which D-serine acts as a potent agonist, [3H]D-serine has also been shown to bind to a novel site in the brain tissues. Moreover, we have observed a profound reduction of cortical D-serine contents in the patients with non-ketotic hyperglycinemia lacking activity of glycine cleavage system (GCS) and in the animal treated with an inhibitor of GCS,cysteamine. Systemic administration of a high amount of L-serine produced a marked increase in cortical D-serine concentrations in the infant rats, vice versa. The present findings further support the view that endogenous D-serine may be involved in the synaptic transmission mediated by the NMDA receptor and other unknown receptor sites. The synthesis of D-serine might be closely related to the metabolism of L-serine and glycine.