Potential Role for Astroglial d-Amino Acid Oxidase in Extracellular d-Serine Metabolism and Cytotoxicity

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Abstract
D-Amino acid oxidase (DAO) is a flavoenzyme that catalyzes the oxidation of d-amino acids. In the brain, gene expression of DAO is detected in astrocytes. Among the possible substrates of DAO in vivo, d-serine is proposed to be a neuromodulator of the N-methyl-d-aspartate (NMDA) receptor. In a search for the physiological role of DAO in the brain, we investigated the metabolism of extracellular d-serine in glial cells. Here we show that after d-serine treatment, rat primary type-1 astrocytes exhibited increased cell death. In order to enhance the enzyme activity of DAO in cells, we established stable rat C6 glial cells overexpressing mouse DAO designated as C6/DAO. Treatment with a high dose of d-serine led to the production of hydrogen peroxide (H2O2) followed by apoptosis in C6/DAO cells. Among the amino acids tested, d-serine specifically exhibited a significant cell death–inducing effect. DAO inhibitors, i.e., sodium benzoate and chlorpromazine, partially prevented the death of C6/DAO cells treated with d-serine, indicating the involvement of DAO activity in d-serine metabolism. Overall, we consider that extracellular d-serine can gain access to intracellular DAO, being metabolized to produce H2O2. These results support the proposal that astroglial DAO plays an important role in metabolizing a neuromodulator, d-serine.