N-Methyl-d-Aspartate receptor and inflammation in dorsolateral prefrontal cortex in schizophrenia.

Lower N-methyl-d-aspartate receptor (NMDAR) GluN1 subunit levels and heightened neuroinflammation are found in the cortex in schizophrenia. Since neuroinflammation can lead to changes in NMDAR function, it is possible that these observations are linked in schizophrenia. We aimed to extend our previous studies by measuring molecular indices of NMDARs that define key functional properties of this receptor - particularly the ratio of GluN2A and GluN2B subunits - in dorsolateral prefrontal cortex (DLPFC) from schizophrenia and control cases (37/37). We sought to test whether changes in these measures are specific to the subset of schizophrenia cases with high levels of inflammation-related mRNAs, defined as a high inflammatory subgroup. Quantitative autoradiography was used to detect 'functional' NMDARs ([3H]MK-801), GluN1-coupled-GluN2A subunits ([3H]CGP-39653), and GluN1-coupled-GluN2B subunits ([3H]Ifenprodil). Quantitative RT-PCR was used to measure NMDAR subunit transcripts (GRIN1, GRIN2A and GRIN2B). The ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were calculated as an index of putative NMDAR composition. We found: 1) GluN2A binding, and 2) the ratios of GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNAs were lower in schizophrenia cases versus controls (p < 0.05), and 3) lower GluN2A:GluN2B binding and GRIN2A:GRIN2B mRNA ratios were exaggerated in the high inflammation/schizophrenia subgroup compared to the low inflammation/control subgroup (p < 0.05). No other NMDAR-related indices were significantly changed in the high inflammation/schizophrenia subgroup. This suggests that neuroinflammation may alter NMDAR stoichiometry rather than targeting total NMDAR levels overall, and future studies could aim to determine if anti-inflammatory treatment can alleviate this aspect of NMDAR-related pathology.

GluN2B protein deficits in the left, but not the right, hippocampus in schizophrenia.

BACKGROUND: Increasing evidence indicates that alterations to the function and subunit composition of the glutamatergic NMDA receptor are associated with the pathophysiology of schizophrenia. The GluN2B protein is a structural and functional subunit of the NMDA receptor, with a growing body of evidence indicating it plays a critical role in cognitive functions mediated by the NMDA receptor. The hippocampus plays a key role in cognitive function, with studies suggesting lateralised glutamatergic dysfunction in this region may contribute to the cognitive deficits observed in schizophrenia patients. The present study, for the first time, investigated GluN2B protein and binding density in the left and right hippocampus of 20 schizophrenia subjects compared to 20 matched controls. METHODS: The dentate gyrus of 20 schizophrenia and 20 control subjects, matched for age, post-mortem interval, and pH, was obtained from the NSW Tissue Resource Centre, Australia. Each group consisted of dentate gyrus from the left hemisphere (n = 10) and right hemisphere (n = 10). GluN2B protein density was measured via immunoblotting. GluN2B binding density was measured using the GluN2B antagonist, [3H] Ifenprodil. Analyses of covariance, covarying for demographic variables that influenced the data, were used to test for statistical significance between schizophrenia and control groups. Pearson's correlations were used to determine the association of GluN2B protein and binding density with demographic and clinical variables, including lifetime antipsychotic drug exposure. RESULTS: GluN2B protein levels were decreased by 43% in the left hemisphere of schizophrenia subjects compared to controls (p = 0.012). There was no difference in GluN2B protein levels in the right hemisphere of schizophrenia subjects compared to controls. There were no differences in [(3)H] Ifenprodil binding according to diagnosis or hemisphere. There were no associations between GluN2B measures and lifetime antipsychotic drug exposure. CONCLUSIONS: Our findings provide the first evidence of GluN2 protein abnormalities in the hippocampus in schizophrenia, highlighting the hippocampal lateralisation in this disorder. We suggest this deficit could contribute to the cognitive dysfunctions that arise in patients. These findings provide preliminary support for the development of therapeutics that target the GluN2B subunit, as a novel therapy for schizophrenia, especially the cognitive dysfunctions.

Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia.

Schizophrenia is a debilitating neurodevelopmental psychiatric disorder. Both the N-methyl-D-aspartate receptor (NMDAR) and neuregulin1 (NRG1) are key molecules involved in normal brain development that have been linked to schizophrenia pathology and aetiology. The NR2 proteins are critical structural and functional subunits of the NMDAR and are developmentally and spatially regulated. Altered NR2 gene and protein expression has been found in human post-mortem schizophrenia brain tissue together with changes in NRG1 and its receptor ErbB4. The NR2 subunits and ErbB4 share a common anchoring domain on the postsynaptic density and therefore a disruption to either of these molecules may influence the functioning of the other. It has been shown that NRG1 signalling can affect NMDAR levels and function, particularly phosphorylation of the NR2 subunits. However little is known about the possible effects of NMDAR dysfunction on NRG1 signalling, which is important with regards to schizophrenia aetiology as numerous risk factors for the disorder can alter NMDAR functioning during early brain development. This review focuses on the role of the NMDA receptor subunits and NRG1 signalling in schizophrenia and proposes a mechanism by which a disruption to the NMDAR, particularly via altering the balance of NR2 subunits during early development, could influence NRG1 signalling.