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

• Published in: Schizophrenia research Vol. 90; no. 1; pp. 41 - 51
• Main Authors: Bendikov, Inna, Nadri, Carmit, Amar, Shirly, Panizzutti, Rogerio, De Miranda, Joari, Wolosker, Herman, Agam, Galila
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.02.2007; Elsevier Science
• Subjects: Adolescent; Adult; Adult and adolescent clinical studies; Aged; Biological and medical sciences; Brain - pathology; Brain - physiopathology; CSF; d-Amino acid oxidase; D-Amino-Acid Oxidase - cerebrospinal fluid; d-Serine; Female; Frontal Lobe - pathology; Frontal Lobe - physiopathology; Glutamic Acid - cerebrospinal fluid; Glutamine - cerebrospinal fluid; Hippocampus - pathology; Hippocampus - physiopathology; Humans; Male; Medical sciences; Middle Aged; Parietal Lobe - pathology; Parietal Lobe - physiopathology; Postmortem brain; Psychiatric/Mental Health; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Racemases and Epimerases - cerebrospinal fluid; Reference Values; Schizophrenia; Schizophrenia - cerebrospinal fluid; Schizophrenia - pathology; Serine - cerebrospinal fluid; Serine racemase; DAAO; CSF; d-Amino acid oxidase; NMDA; Schizophrenia; Serine racemase; Postmortem brain; d-Serine; SR; serine racemase; N-methyl d-aspartate; cerebro-spinal fluid; d-amino acid oxidase; Human; Enzyme; Serine; D-Serine; Central nervous system; Postmortem; D-Amino-acid oxidase; Cerebrospinal fluid; Encephalon; Psychosis; D-Amino acid oxidase; Aminoacid; Oxidoreductases
• ISSN: 0920-9964; 1573-2509
• DOI: 10.1016/j.schres.2006.10.010

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.