Does the distribution of free D-serine, which is a potent activator of the NMDA receptor complex, coincide with the localization of D-amino acid oxidase in brains?

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D-Serine is a potent activator of the NMDA receptor complex. In various brain regions of the lower vertebrate species, D-serine levels were low. On the contrary, in the mammals, the contents of free D-serine were high in the forebrain (ca.400 nmol/g wet weight, the D/L ratio =0.4) , and low in the hindbrain. Free D-serine was shown not to be of microbial origin using germ-free mice.D-Serine binding in rat brain was high in the forebrain, especially the hippocampus, indicating that the distribution of NMDA receptor is high in the forebrain.D-Amino acid oxidase was absent or scarce in the forebrain, and was confined to the brain stem, spinal cord, and cerebellum. The oxidase-containing cells were exclusively astrocytes including Bergmann glial cells, and neither neuronal components, endothelial cells, oligodendrocytes nor ependymal cells showed the oxidase activity. The greater proportion of the oxidase activity was preset in the glial spaces around various kinds of synapses, and the activity was not associated with a specific kind of neuron, synapse or transmitter.The astrocytes regionally differentiate into two distinct types, one of which expresses the oxidase in the midbrain, rhombencephalon and spinal cord, and the other which dose not in the forebrain. That is, the oxidase gene expression is regulated in a regionally all-or-none fashion in the astrocytes. In the mammalian brains, the distribution of the oxidase is inversely correlated with those of free D-serine and NMDA receptor. These results indicate that the oxidase decomposes free D-amino acids including D-serine in the brain, and that the magnitude of its activity (the specific activity) is important in determining the regional concentrations of D-amino acids in the steady state.