Rhodes, C. H. | Search bioRxiv

bioRxiv2021

Differential sphingosine-1-phosphate receptor-1 (S1PR1) protein expressions in the dorsolateral prefrontal cortex between schizophrenia Type 1 and Type 2

Understanding the etiology and treatment approaches in schizophrenia is challenged in part by the heterogeneity of this disorder. One encouraging progress is the growing evidence that there are subtypes of schizophrenia that may relate to disease duration and premorbid severity. Recent in vitro findings of messenger ribonucleic acid (mRNA) gene expression on postmortem dorsolateral prefrontal cortex (DLPFC) showed that schizophrenia has two subtypes, those with a relatively normal DLPFC transcriptome (Type 1) and those with differentially expressed genes (Type 2). Sphingosine-1-phosphate receptor-1 (S1PR1) is one of the genes that was highly upregulated in Type 2 compared to Type 1 and controls. The impact of that finding is limited because it only can be confirmed through analysis of autopsy tissue, and the clinical characteristics such as symptoms severity or illness duration was not available from that Medical Examiner based autopsy study. However, S1PR1 has great potential because it is a target gene that can be accessed via positron emission tomography (PET) in vivo using specific radioligands (starting with [11C]CS1P1) successfully developed at our center in human brain imaging. As a preliminary study to validate this PET target in schizophrenia, S1PR1 protein expression was assessed by receptor autoradiography (ARG) using [3H]CS1P1 and immunohistochemistry (IHC) in the DLPFC from patients with schizophrenia classified as Type 1 or Type 2 based on their DLPFC transcriptomes and from controls. Our analyses demonstrate that ARG S1PR1 protein expression is significantly higher in Type 2 compared to Type 1 (p < 0.05) and controls (p < 0.05), which was consistent with previous mRNA S1PR1. These findings support the possibility that PET S1PR1 can be used as a future imaging biomarker to distinguish these subgroups of schizophrenic patients during life with obvious implications for both patient management and the design of clinical trials to validate novel pharmacologic therapies.

neuroscience↗

bioRxiv2017

DLPFC Transcriptome Defines Two Molecular Subtypes of Schizophrenia

The Clinical Brain Disorders Branch of the Intramural Research Program at the National Institutes of Health assembled a large collection of frozen post-mortem human brains from individuals diagnosed with schizophrenia and other psychiatric diagnoses, as well as matched control individuals. Illumina HumanHT-12 v4 expression array data was collected from dorsolateral prefrontal cortex (DLPFC) and the data deposited at dbGaP (Study ID: phs000979). We report an analysis of the data from the 189 adult schizophrenics and 206 adult controls in that cohort.\n\nTranscripts from 633 genes are differentially expressed in the DLPFC of schizophrenics as compared to the controls at levels of statistical significance which survive Bonferroni correction. Seventeen of those genes are differentially expressed at a level of statistical significance less than 10-8 after Bonferroni correction.\n\nWeighted Gene Co-expression Network Analysis (WGCNA) of the schizophrenic subjects using differentially expressed gene module eigengenes divides them into two groups, \"type 1\" and \"type 2.\" There are 2,635 genes differentially expressed in the DLPFC of type 2 schizophrenics at a level of statistical significance which survives Bonferroni correction. Of them 221 have P-values less than 10-15 after Bonferroni correction. In the type 1 schizophrenics however, only 6 genes are differentially expressed in the DLPFC at a level of statistical significance which survives Bonferroni correction. This striking difference in their DLPFC transcriptomes emphasizes the fundamental biologic difference between these two groups of patients.

neuroscience↗