Translational alterations of retinoid receptors, their binding partners and the retinoid signalling pathway in schizophrenia brain and blood

Abstract

Schizophrenia is a debilitating mental illness characterised by positive, negative and cognitive symptoms. Epidemiological studies implicate vitamin D in the aetiology of schizophrenia and protein studies show altered circulating levels of the ligand vitamin D and implicate retinoids in schizophrenia. However, the gene expressions of vitamin D and retinoid receptors have not been extensively studied. In parallel, there is increasing interest in the role of neuroinflammation in the aetiology and progression of schizophrenia and both vitamin D and retinoids (vitamin A and its derivatives) have known anti-inflammatory actions

My thesis aims to measure expression of molecules involved in vitamin D and retinoid signalling and determine the influence of elevated inflammatory markers on these molecules. My findings are obtained from two cohorts: a post-mortem brain cohort comprising tissue samples from the frontal cortex from thirty-seven individuals with schizophrenia and thirty-seven matched controls; and a clinical cohort of eighty-six patients with schizophrenia and seventy-seven controls who provided peripheral blood samples.

Firstly, I used next generation sequencing data and real-time polymerase chain reaction in the post-mortem brain cohort to identify decreased mRNA expression of one retinoid X receptor subtype (RXRB) and of two of its binding partners, the NR4A1 and NR4A2 receptors, in schizophrenia.

Secondly, using previously identified subgroups of people with neuroinflammation in the post-mortem cohort, I found that expression of two receptors, RXRB and retinoic acid receptor gamma (RARG), were increased in schizophrenia with neuroinflammation, whereas two orphan nuclear receptors, NR4A1 and NR4A3, were decreased in the same group.

Finally, I analysed mRNA transcript levels in blood, and identified dysregulation in the retinoid signalling pathway in schizophrenia, principally involving the disruption of the conversion of retinol to retinoic acid (the bioactive form of vitamin A). I also found evidence of crosstalk between retinoid signalling molecules and pro-inflammatory cytokines. The dysregulation in gene transcripts of the retinoid signalling pathway also affected cognitive performance on tasks involving the prefrontal cortex and hippocampus.

My studies suggest retinoids contribute to the aetiology of schizophrenia and identify a direct relationship with pro-inflammatory cytokines in both brain and blood.