Nuclear Receptors and Neuroinflammation in Schizophrenia

Introduction: Several nuclear receptor family members have been associated with schizophrenia and inflammation. Vitamins A and D exert anti-inflammatory actions, but their receptors (mainly nuclear receptors) have not been extensively studied in either schizophrenia brains or in association with neuroinflammation. We examined the expression of vitamin A (RARs and RXRs) and vitamin D and protein disulphide-isomerase A3 (PDIA3) receptors, as well as nuclear orphan receptors (NR4As), in the context of elevated cytokine expression in the dorsolateral prefrontal cortex (DLPFC).

Methods: mRNA levels of nuclear receptors were measured in DLPFC tissues via RT-qPCR. ANCOVAs comparing high inflammation schizophrenia, low inflammation schizophrenia and low inflammation control groups were performed.

Results: RARG, RXRB, NR4A1 and NR4A3 transcripts showed significant differential expression across the three groups (ANCOVA p = 0.02-0.001). Post hoc testing revealed significant reductions in RARG expression in schizophrenia with low inflammation compared to schizophrenia with high inflammation and to controls, and RXRB mRNA was significantly reduced in schizophrenia with low inflammation compared to controls. NR4A1 and NR4A3 mRNAs were decreased in schizophrenia with high inflammation compared to schizophrenia with low inflammation, with NR4A1 also significantly different to controls.

Conclusion: In schizophrenia, changes in nuclear receptor mRNA levels involved with mediating actions of vitamin A derivatives vary according to the inflammatory state of brains.