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

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.

GluN2D N-Methyl-D-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia

“…However, GluN2B-selective antagonists were found to better augment kainate-induced gamma oscillations than a GluN2A-preferring antagonist (McNally et al, 2011). GluN2C involvement in schizophrenia is suggested by the finding that GluN2C transcript levels are significantly reduced in schizophrenia patients (Weickert et al, 2013) and by the presence of working memory and fear acquisition defects in GluN2C-KO mice (Hillman et al, 2011). A potential role of GluN2C subunits in schizophrenia is also suggested by GluN2C expression in the reticular nucleus of the thalamus, which modulates hippocampal delta oscillations and thus may explain the delta oscillatory changes seen in schizophrenia patients .…”

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

“…Pharmacologic and biochemical evidence has converged to support NMDAR hypofunction as a key etiological component of schizophrenia (23)(24)(25)(26). Furthermore, meta-analysis of genetic association studies (27) and recent large-scale, copy number variants analyses (28,29) have implicated the NMDAR and proteins associated with the postsynaptic density in the etiology of schizophrenia.…”

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

“…Reduced NMDA-R expression in several brain regions, including the frontal cortex and hippocampus, has been found in individuals with schizophrenia (Errico et al, 2013;Geddes et al, 2014Geddes et al, , 2011Weickert et al, 2013). GABAA-R expression level differences vary between receptor subtypes and brain regions in individuals with schizophrenia (Benes et al, 1996a(Benes et al, , 1996bDuncan et al, 2010).…”

“…Substantial evidence from human and animal studies links an imbalance of excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmission to the pathophysiology of schizophrenia (Javitt, 2010;Nakazawa et al, 2012). Recent studies report reduced expression of glutamatergic N-methyl-D-aspartate receptors (NMDA-R) and suggest an increase in glutamatergic state via activation of non-NMDA glutamate receptors in individuals with schizophrenia (Geddes et al, 2011;Hu et al, 2014;Moghaddam and Javitt, 2012;Nakazawa et al, 2012;Weickert et al, 2013). Furthermore, reduced expression levels of GABA synthesizing enzymes and transporters together with increased expression of GABAA receptors (GABAA-R) have been identified in several disease-relevant brain regions in individuals with schizophrenia (recently reviewed by Inan et al, 2013).…”