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

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. and Weickert, T. W. (2013) Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Molecular Psychiatry, 18 11: 1185-1192. doi:10.1038/mp.2012.137


Author 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.
Title Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia
Formatted title
Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia
Journal name Molecular Psychiatry   Check publisher's open access policy
ISSN 1359-4184
Publication date 2013-11-01
Year available 2012
Sub-type Article (original research)
DOI 10.1038/mp.2012.137
Open Access Status DOI
Volume 18
Issue 11
Start page 1185
End page 1192
Total pages 8
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1312 Molecular Biology
2804 Cellular and Molecular Neuroscience
2738 Psychiatry and Mental health
Abstract 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.
Formatted abstract
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.
Keyword Cognition
Expression
NMDA receptor
Prefrontal cortex
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 568807
Institutional Status UQ
Additional Notes Published online 16 October 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
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Created: Sat, 24 Nov 2012, 23:30:35 EST by Matthew Lamb on behalf of School of Medicine