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.