University of Wollongong
Browse

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

Download (882.5 kB)
journal contribution
posted on 2024-11-14, 22:26 authored by C S Weickert, S J Fung, V S Catts, P R Schofield, K M Allen, L T Moore, Kelly NewellKelly Newell, D Pellen, Xu-Feng HuangXu-Feng Huang, S V Catts, T W Weickert
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.

History

Citation

Weickert, C. S., Fung, S., Catts, V. S., Schofield, P., Allen, K., Moore, L. T., Newell, K. A., Pellen, D., Huang, X., Catts, S. and Weickert, T. (2013). Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Molecular Psychiatry, 18 (11), 1185-1192.

Journal title

Molecular Psychiatry

Volume

18

Issue

11

Pagination

1185-1192

Language

English

RIS ID

75707

Usage metrics

    Categories

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC