Regulation of neural D-serine metabolism and its application for the development of novel treatment of schizophrenia

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In this study we have been focusing on the regulation of D-serine metabolism in the mammalian brain and its clinical application for the development of novel treatment of drug-resistant schizophrenic symptoms. Recent investigations by us and others indicated possible involvement of dysfunction of glutamatergic signaling in the pathophysiology of both positive and negative symptoms of schizophrenia D-serine is an endogenous co-agonist of NMDA type glutamate receptors. We have isolated and characterized D-serine-modulator-1 (dsm-1) gene, which may play a crucial role in the regulation of cellular D-serine release in the central nervous system. Also, we determined the effect of glial toxins on the extracellular D-serine concentration of the rat brain. The obtained results implicated that glial cells are much involved in the regulation of D-serine metabolism in the mammalian brain Recent clinical trials for schizophrenia suggested that D-serine, glycine and D-cycloserine, as allosteric agonists of the NMDA receptors should be strong candidates of the novel generation antipsychotics. Curiously, we have found D-cycloserine selectively modulate the extracellular concentration of neural D-serine. Further studies should be able us to understand molecular and cellular mechanism of the regulation of neural D-serine metabolism and the development of novel pharmacotherapy of schizophrenia.