Abstract
Many genes are differentially expressed in the cortex of people with schizophrenia, implicating factors that control transcription more generally. Hormone nuclear receptors dimerize to coordinate context-dependent changes in gene expression. We hypothesized that members of two families of nuclear receptors (NR4As), and retinoid receptors (RARs and RXRs), are altered in the dorsal lateral prefrontal cortex (DLPFC) of people with schizophrenia. We used next generation sequencing and then qPCR analysis to test for changes in mRNA levels for transcripts encoding nuclear receptors: orphan nuclear receptors (3 in the NR4A, 3 in the RAR, 3 in the RXR families and KLF4) in total RNA extracted from the DLPFC from people with schizophrenia compared to controls (n = 74). We also correlated mRNA levels with demographic factors and with estimates of antipsychotic drug exposure (schizophrenia group only). We tested for correlations between levels of transcription factor family members and levels of genes putatively regulated by these transcription factors. We found significantly down regulated expression of NR4A1 (Nurr 77) and KLF4 mRNAs in people with schizophrenia compared to controls, by both NGS and qPCR (p = or <0.01). We also detected decreases in NR4A2 (Nurr1) and RXRB mRNAs by using qPCR in the larger cohort (p<0.05 and p<0.01, respectively). We detected decreased expression of RARG and NR4A2 mRNAs in females with schizophrenia (p<0.05). The mRNA levels of NR4A1, NR4A2 and NR4A3 were all negative correlated with lifetime estimates of antipsychotic exposure. These novel findings, which may be influenced by antipsychotic drug exposure, implicate the orphan and retinoid nuclear receptors in the cortical pathology found in schizophrenia. Genes down stream of these receptors can be dysregulated as well, but the direction of change is not immediately predictable based on the putative transcription factor changes.
Highlights
Schizophrenia is a serious psychiatric disorder adversely affecting the quality of life of a significant number of people [1]
Our analysis indicates that NR4A1 falls within the moderately expressed cluster and is expressed at similar abundance levels as the other members of this sub-family NR4A2 (Nurr1) and NR4A3 (Nor-1)
As we were interested in seeing the relative expression levels of the nuclear receptors in the dorsal lateral prefrontal cortex (DLPFC) we adjusted for gene length and clustered by gene name rather than by sample
Summary
Schizophrenia is a serious psychiatric disorder adversely affecting the quality of life of a significant number of people [1]. Schizophrenia arises from a complex and varied set of environmental and genetic factors, which has made it very difficult to come to a clear understanding of the etiology of the condition, despite intensive scientific work in the area. It seems that a disease arising from the interplay of genes and environment is likely to involve the super family of nuclear receptors which are known to control gene expression depending on context. The nuclear receptors generally dimerize to form either homodimers or heterodimers with other nuclear receptors and may be activated by multiple ligands They are part of a complex network of molecules essential for development and adaptive responses in the adult
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