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

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

Disclosures

Schizophr Bull. 2020;46(5):1172-1181. 

In This Article

Abstract and Introduction

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.

Introduction

Although 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.[1–4] 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.[4–7] 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.[8–10] However, the mechanism underlying these observations is unclear. Recently, 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. Of note, metabolic abnormalities of sphingolipids, which are serine-derived lipids, were also observed.[15–17]

Sphingolipids form the key structural component of plasma membranes and are essential for the development and normal function of the brain. Biosynthesis of most sphingolipids starts with the condensation of palmitoyl-CoA and amino acid L-serine by serine palmitoyltransferase (SPT), and some with alanine or glycine (the final product is 1-deoxy-sphinganine or 1-deoxymethyl-sphinganine) (Figure 1A).[18–22] There are 2 types of sphingolipids: base form and fatty-acid-acylated form. The base form includes sphingosine-1-phosphate (S1P) and sphingosine (SO), and the fatty-acid-acylated form includes ceramide (Cer) and sphingomyelin (SM) (Figure 1A). Sphingosine-1-phosphate is serine-derived and acts as a signaling molecule; it is involved in the regulation of various functions, such as myelination, differentiation of oligodendrocytes, hematopoietic cell trafficking, autophagy, and immune-cell fate via S1P receptors.[23–25]

Figure 1.

Sphingoid base levels in postmortem human and mouse brains. (A) Sphingolipid synthesis pathway. Sphingolipid biosynthesis starts with the condensation of palmitoyl-CoA and L-serine by serine palmitoyltransferase (SPT). Then, sphinganine (SA), dihydroceramide (DHCer), ceramide (Cer), sphingosine (SO), and sphingosine-1-phosphate (S1P) are serially synthesized. Furthermore, not only L-serine (Ser) but also L-alanine (Ala) or glycine (Gly) is used to generate sphingoid bases. Lipids were analyzed for sphingoid base levels from (B) the corpus callosum and (C) Brodmann area 8. S1P levels are low in the corpus callosum of patients with schizophrenia. The levels of doxSO and doxmeSO are below the detection limits in the corpus callosum and BA8, limiting their quantification. (D) The ratio of the sum of SO and Cer to S1P in the human corpus callosum and Brodmann area 8. (B–D) Data are represented as the mean ± SEM. N.D., not determined; **P < .01. Differences between 2 groups were analyzed by Mann-Whitney U test. (E) Administration of antipsychotic drugs did not affect S1P levels in the corpus callosum and frontal cortex of mice. Data are represented as the mean ± SEM. **P < .01. Differences among 3 groups were analyzed by non-parametric Kruskal-Wallis analysis, followed by Dunnett's test (vs vehicle group).

Previous studies have shown that levels of SM and Cer were reduced in postmortem brain and skin samples, respectively, from patients with schizophrenia.[16,26] Furthermore, an altered expression level of the gene for SPT long chain base subunit 2 (SPTLC2), 1 of 3 different subunits of SPT, was observed in brain samples from patients with schizophrenia.[27] However, the role of sphingolipids in schizophrenia has not been sufficiently addressed.

We performed a systematic analysis of sphingolipid levels and an expression analysis of genes for sphingolipid metabolism in the corpus callosum (representative white matter) and Brodmann area 8 (BA8; frontal cortical area) of postmortem brain samples from patients with schizophrenia and age-/sex-matched controls. Subsequently, we looked for altered sphingolipids in postmortem brain samples from patients with major depression and bipolar disorder and compared them with the controls to determine whether the dysregulation is specific to schizophrenia or a global phenomenon seen in other psychiatric disorders. Furthermore, we used mice to examine the effects of antipsychotics on the sphingolipid metabolism.

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