Differential Sphingosine-1-Phosphate Receptor-1 Protein Expression in the Dorsolateral Prefrontal Cortex Between Schizophrenia Type 1 and Type 2

Abstract

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. 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 except for cause of death 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.

SMAD genes are up‐regulated in brain and blood samples of individuals with schizophrenia

“…Interestingly, it was shown that the protein encoded by S1PR1 can be accessed via positron emission tomography (PET) in vivo using specific radioligands. Both the mRNA and the S1PR1 protein levels were found to be up-regulated in schizophrenia "Type 2," and it was suggested as a future imaging biomarker to distinguish between schizophrenia "Type 1" and "Type 2" subgroups (Chand et al, 2022), that were mentioned above (Bowen et al, 2019).…”

Potential of olfactory neuroepithelial cells as a model to study schizophrenia: A focus on GPCRs (Review)

“…Recent targeted mass spectrometry-based analysis found that postmortem samples of the corpus callosum of patients with SZ have lower levels of S1P ( 268 ). Furthermore, one study divided patients with SZ into those that present an upregulation of S1PR1 and those that have levels comparable to controls ( 269 ). This may be used as a biomarker since S1PR1 can be detected through positron emission tomography ( 269 ).…”

“…Furthermore, one study divided patients with SZ into those that present an upregulation of S1PR1 and those that have levels comparable to controls ( 269 ). This may be used as a biomarker since S1PR1 can be detected through positron emission tomography ( 269 ).…”

Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain

“…In the central nervous system (CNS), S1PR1 is expressed in neurons, astrocytes, microglia, and oligodendrocytes and plays an important role in neural development and neuroinflammatory processes . Recent studies have demonstrated that S1PR1 is involved in several CNS disorders including multiple sclerosis (MS), traumatic brain injuries, neuropathic pain, and schizophrenia …”