Functional analysis and expression cloning of D-serine uptake site

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Although D-amino acids have been assumed to be unnatural in mammals, a wide variety of studies has demonstrated that free D-serine and serine racemase occur in the mammalian brain. To gain an insight into the uptake site of D-serine, we have investigated the effect of systemic administration of D-serine on the concentrations of D- and L-serine in the several brain areas and periphery of infant and adult rat. Intraperitoneal administration of D-serine caused a drastic increase in the levels of D-serine in all brain areas and periphery of infant and adult rat. The increase in the D-serine levels were higher in the cerebellum and kidney, which D-amino acid oxidase appear during early postnatal development. A systemic injection of D-serine produced a slight but significant increase in the levels of L-serine in almost all brain and peripheral tissues of infant rat. The increase in the L-serine levels might be due to the reverse reaction of serine racemase. Following a systemic injection of D-serine, the D-serine concentrations in all brain areas of adult rat rapidly increased, and peaked at 3 or 6 hours. The D-serine levels in the cortex, striatum, hippocampus, diencephalon gradually decreased and returned to the control levels 7 days after the injection, whereas the D-serine levels in the pons-medulla and cerebellum rapidly decreased and returned to the control levels 3 days after the injection. Because D-serine potentiates the NMDA receptor-mediated neurotransmission via the glycine site with an affinity similar to glycine and because D-serine application ameliorates the positive and negative symptoms of schizophrenia, D-serine administration could be beneficial in treating diseases related to the hypofunction of the NMDA-mediated neurotransmission such as schizophrenia and Alzheimer's disease.