Evidence for Altered Metabolism of Sphingosine-1-Phosphate in the Corpus Callosum of Patients with Schizophrenia.

Chie Shimamoto-Mitsuyama,Kayoko Esaki,Takeo Yoshikawa,Brian Dean,Shabeesh Balan,Yoshimi Iwayama,Yoshio Hirabayashi

doi:10.1093/schbul/sbaa052

Abstract

The disturbed integrity of myelin and white matter, along with dysregulation of the lipid metabolism, may be involved in schizophrenia pathophysiology. Considering the crucial role of sphingolipids in neurodevelopment, particularly in oligodendrocyte differentiation and myelination, we examined the role of sphingolipid dynamics in the pathophysiology of schizophrenia. We performed targeted mass spectrometry-based analysis of sphingolipids from the cortical area and corpus callosum of postmortem brain samples from patients with schizophrenia and controls. We observed lower sphingosine-1-phosphate (S1P) levels, specifically in the corpus callosum of patients with schizophrenia, but not in major depressive disorder or bipolar disorder, when compared with the controls. Patient data and animal studies showed that antipsychotic intake did not contribute to the lowered S1P levels. We also found that lowered S1P levels in the corpus callosum of patients with schizophrenia may stem from the upregulation of genes for S1P-degrading enzymes; higher expression of genes for S1P receptors suggested a potential compensatory mechanism for the lowered S1P levels. A higher ratio of the sum of sphingosine and ceramide to S1P, which can induce apoptosis and cell-cycle arrest, was also observed in the samples of patients with schizophrenia than in controls. These results suggest that an altered S1P metabolism may underlie the deficits in oligodendrocyte differentiation and myelin formation, leading to the structural and molecular abnormalities of white matter reported in schizophrenia. Our findings may pave the way toward a novel therapeutic strategy.

Highlights

IntroductionThe neurobiological mechanism of schizophrenia remains largely elusive, reduced white matter in the brain has been consistently reported in patients with schizophrenia and shown to be correlated with negative symptoms.[1,2,3,4] In particular, diffusion tensor imaging (DTI), which measures water diffusion within the axon or myelin sheath, showed a significant reduction in fractional anisotropy (FA) in regions of the brain, including the corpus callosum, in patients with schizophrenia.[4,5,6,7] This decrease in FA may indicate abnormalities of myelination and oligodendrocyte functions; postmortem brain tissues of patients with schizophrenia revealed impairments of the myelin-sheath lamellae, reduction in the area of the nucleus and the volume density of mitochondria in oligodendrocytes, and downregulation of myelin-related genes.[8,9,10] the mechanism underlying these observations is unclear
We were the first to demonstrate that S1P levels were significantly reduced in the corpus callosum of patients with schizophrenia
We showed that the lowered S1P level was accompanied by an increase in the expression of gene(s) for S1P-degrading enzyme(s) Phospholipid Phosphatase 3 (PLPP3)

Summary

Introduction

The neurobiological mechanism of schizophrenia remains largely elusive, reduced white matter in the brain has been consistently reported in patients with schizophrenia and shown to be correlated with negative symptoms.[1,2,3,4] In particular, diffusion tensor imaging (DTI), which measures water diffusion within the axon or myelin sheath, showed a significant reduction in fractional anisotropy (FA) in regions of the brain, including the corpus callosum, in patients with schizophrenia.[4,5,6,7] This decrease in FA may indicate abnormalities of myelination and oligodendrocyte functions; postmortem brain tissues of patients with schizophrenia revealed impairments of the myelin-sheath lamellae, reduction in the area of the nucleus and the volume density of mitochondria in oligodendrocytes, and downregulation of myelin-related genes.[8,9,10] the mechanism underlying these observations is unclear. Several studies have reported an altered metabolism of lipids[11,12] and amino acid serine[13,14] in postmortem brain and blood samples, respectively, from patients with schizophrenia. Metabolic abnormalities of sphingolipids, which are serine-derived lipids, were observed.[15,16,17]

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Results

Conclusion