Law AJ, Deakin JF. Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. NeuroReport 12: 2971-2974

Department of Neuropathology, University of Oxford, Radcliffe Infirmary, Gibson Building, Woodstock Road, Oxford, OX2 6HE, UK.
Neuroreport (Impact Factor: 1.52). 10/2001; 12(13):2971-4. DOI: 10.1097/00001756-200109170-00043
Source: PubMed


The psychotomimetic properties of NMDA glutamate receptor antagonists suggest there may be disease related changes of this receptor in schizophrenia. Using in situ hybridisation histochemistry (ISHH), we measured mRNA for the obligatory NMDAR1 subunit of the NMDA glutamate receptor in post-mortem samples of hippocampus from schizophrenics, depressives, bipolar patients and normal controls. A significant main effect of diagnosis was observed in the dentate gyrus (ANOVA, p = 0.004) and a trend in the CA3 region (ANOVA, p = 0.06), with all psychiatric groups having reduced NMDAR1 mRNA levels compared to normal controls. In contrast to the affectively ill groups, the reductions in schizophrenics were more pronounced in the left side compared to the right. Expression of poly A mRNA also showed left-sided losses in the dentate gyrus in schizophrenia but reductions in NMDAR1 remained significant when expressed as a ratio of poly A. The findings confirm a recent report of reduced hippocampal NMDAR1 mRNA in schizophrenia. However, our new evidence suggests that this is a feature of both affective and schizophrenic disorders and that schizophrenia is distinguished from the others by left-sided reductions in hippocampal NMDAR1 gene expression.

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    • "However, there was a decrease in the CHF groups which had been subjected to stress within the hippocampus, amygdala and NAc, suggesting that the low levels of NMDAR1 may be related to a commonality between anxiety and depression. Interestingly, it was also shown that there was a reduction in NMDAR1 mRNA levels within the dentate gyrus and CA3 regions of post-mortem samples taken from schizophrenics, depressives and bipolar patients [38]. "
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    ABSTRACT: This study aimed at investigating the effects of chronic mild stress on DNA damage, NMDA receptor subunits and glutamate transport levels in the brains of rats with an anxious phenotype, which were selected to represent both the high-freezing (CHF) and low-freezing (CLF) lines. The anxious phenotype induced DNA damage in the hippocampus, amygdala and nucleus accumbens (NAc). CHF rats subjected to chronic stress presented a more pronounced DNA damage in the hippocampus and NAc. NMDAR1 were increased in the prefrontal cortex (PC), hippocampus and amygdala of CHF, and decreased in the hippocampus, amygdala and NAc of CHF stressed. NMDAR2A were decreased in the amygdala of the CHF and stressed; and increased in CHF stressed. NMDRA2A in the NAc was increased after stress, and decreased in the CLF. NMDAR2B were increased in the hippocampus of CLF and CHF. In the amygdala, there was a decrease in the NMDAR2B for stress in the CLF and CHF. NMDAR2B in the NAc were decreased for stress and increased in the CHF; in the PC NMDAR2B increased in the CHF. EAAT1 increased in the PC of CLF+stress. In the hippocampus, EAAT1 decreased in all groups. In the amygdala, EAAT1 decreased in the CLF+stress and CHF. EAAT2 were decreased in the PC for stress, and increased in CHF+control. In the hippocampus, the EAAT2 were increased for the CLF and decreased in the CLF+stress. In the amygdala, there was a decrease in the EATT2 in the CLF+stress and CHF. These findings suggest that an anxious phenotype plus stress may induce a more pronounced DNA damage, and promote more alterations in the glutamatergic system. These findings may help to explain, at least in part, the common point of the mechanisms involved with the pathophysiology of depression and anxiety. Copyright © 2015 Elsevier B.V. All rights reserved.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2014; 772. DOI:10.1016/j.mrfmmm.2014.12.005 · 3.68 Impact Factor
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    • ", 2009 ; Weickert et al . , 2013 ) but is dissimilar to others ( Law and Deakin , 2001 ; Kristiansen et al . , 2006 ) . "
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    ABSTRACT: Disrupted-in-schizophrenia 1 (DISC1) is a genetic risk factor that has been implicated in major mental disorders. DISC1 binds to and stabilizes serine racemase to regulate production of D-serine by astrocytes, contributing to glutamate (GLU) neurotransmission. However, the possible involvement of astrocytic DISC1 in synthesis, metabolism, reuptake, or secretion of GLU remains unexplored. Therefore, we studied the effects of dominant-negative mutant DISC1 on various aspects of GLU metabolism by using primary astrocyte cultures and hippocampal tissue from transgenic mice with astrocyte-restricted expression of mutant DISC1. Although mutant DISC1 had no significant effects on astrocyte proliferation, GLU reuptake, glutaminase, or glutamate carboxypeptidase II activity, expression of mutant DISC1 was associated with increased levels of alanine-serine-cysteine transporter 2, vesicular glutamate transporters 1 and 3 in primary astrocytes and in the hippocampus, and elevated expression of the NR1 subunit and diminished expression of the NR2A subunit of N-methyl-D-aspartate (NMDA) receptors in the hippocampus, at postnatal day 21. Our findings indicate that decreased D-serine production by astrocytic mutant DISC1 might lead to compensatory changes in levels of the amino acid transporters and NMDA receptors in the context of tripartite synapse. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 12/2014; 92(12). DOI:10.1002/jnr.23459 · 2.59 Impact Factor
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    • "In our study, repeated MK-801 treatment decreased GluN1 mRNA expression in the hippocampus, but not in the frontal cortex and striatum, an effect that was also attenuated by CBD and clozapine. Even if contradictory results exist in the literature (Rujescu et al., 2006), reduction in mRNA expression of this subunit in the hippocampus of schizophrenia patients has been reported (Gao et al., 2000; Law and Deakin, 2001). In addition, a study using a single photon emission tomography ligand for NMDAR revealed that medication-free schizophrenia patients had lower NMDAR binding in the left hippocampus, a change not observed in clozapine-treated patients (Pilowsky et al., 2006). "
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    ABSTRACT: Background: Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801.
    The International Journal of Neuropsychopharmacology 10/2014; 18(5). DOI:10.1093/ijnp/pyu041 · 4.01 Impact Factor
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