A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia

Clinical trials demonstrated that d-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous d-serine may contribute to the N-methyl d-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) d-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and d-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in d-serine levels and d/l-serine ratio in CSF of schizophrenia patients, while parietal-cortex d-serine was unaltered. Levels of l-serine, l-glutamine and l-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/d-amino acid oxidase ratio (34%) were reduced. Hippocampal d-amino-acid-oxidase protein levels significantly correlated with duration of illness (r = 0.6, p = 0.019) but not age. d-amino acid oxidase levels in patients with DOI > 20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated d-amino acid oxidase protein levels may contribute to the lower CSF d-serine levels in schizophrenia.