Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia

• Published in: Molecular psychiatry Vol. 18; no. 11; pp. 1185 - 1192
• Main Authors: Weickert, C S, Fung, S J, Catts, V S, Schofield, P R, Allen, K M, Moore, L T, Newell, K A, Pellen, D, Huang, X-F, Catts, S V, Weickert, T W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2013; Nature Publishing Group
• Subjects: 631/208/726/649; 631/378/1457/1945; 631/378/340; 692/699/476/1799; Adult; Adult and adolescent clinical studies; Alleles; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Brain research; Care and treatment; Case-Control Studies; Causes of; Cognition; Cognition & reasoning; Complications and side effects; Female; Gene expression; Genetic aspects; Genetic Predisposition to Disease - genetics; Genotype; Health aspects; Humans; Male; Medical sciences; Medicine; Medicine & Public Health; Memory; Methyl aspartate; Middle Aged; Neurosciences; Original; original-article; Pharmacotherapy; Physiological aspects; Polymorphism, Single Nucleotide; Prefrontal Cortex - metabolism; Protein Subunits - genetics; Proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenic Psychology; Wechsler Scales; Australia; expression; schizophrenia; cognition; SNP; NMDA receptor; prefrontal cortex; Psychosis; Central nervous system; Schizophrenia; Glutamate receptor; Cognition; Prefrontal cortex; Encephalon
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2012.137

Blockade of N -methyl- D -aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control ( n =74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia ( P =0.004, P =0.01 and P =0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.