D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor

Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although D-serine is a more potent agonist, Localiz ations of D-serine and it biosynthetic enzyme serine racemase approximate t he distribution of NMDA receptors more closely than glycine, We now show th at selective degradation of D-serine with D-amino acid oxidase greatly atte nuates NMDA receptor-mediated neurotransmission as assessed by using whole- cell patch-clamp recordings or indirectly by using biochemical assays of th e sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects o f the enzyme are fully reversed by exogenously applied D-serine, which by i tself did not potentiate NMDA receptor-mediated synaptic responses. Thus, D -serine is an endogenous modulator of the glycine site of NMDA receptors an d fully occupies this site at some functional synapses.