Decreased levels of d-aspartate and NMDA in the prefrontal cortex and striatum of patients with schizophrenia

Abstract

The potential implication of a decrease in the function of N-methyl-d-aspartate receptors (NMDARs) in the pathophysiology of schizophrenia has long been hypothesised. Accordingly, compounds that inhibit the glycine-1 transporter or target the glycine-binding site of NMDARs, including the co-agonists d-serine and glycine, have shown promise in treating the symptoms of schizophrenia. Clinical interest for d-serine has also been supported by evidence for its abnormal metabolism in schizophrenic patients. Together with d-serine, another d-form amino acid, d-aspartate, exists in the brain of mammals. Synthesised by the enzyme aspartate racemase, d-aspartate is highly concentrated in the prenatal brain; after birth, its levels sharply decrease due to the catabolising activity of the enzyme d-aspartate oxidase. d-aspartate is able to stimulate NMDAR-dependent neurotransmission through direct action at the glutamate-binding site of NMDARs, thus functioning as an endogenous agonist for this subclass of glutamate receptors. In this study, we evaluated for the first time the content of d-aspartate and of its derivative, NMDA, in the post-mortem prefrontal cortex and striatum of schizophrenic patients. Moreover, in the same brain samples, we analysed the expression levels of the subunits that form NMDARs, which are the in vivo targets of d-aspartate and NMDA. Interestingly, we found that d-aspartate and NMDA are consistently decreased in schizophrenia brains compared to control brains. In the prefrontal cortex, this decrease is correlated with a marked downregulation of NMDAR subunits. Overall, these results agree with the innovative therapeutic research in schizophrenia that is aimed at targeting glutamatergic transmission viad-amino acids.