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


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

In This Article


To our knowledge, we were the first to demonstrate that S1P levels were significantly reduced in the corpus callosum of patients with schizophrenia. We also showed that the lowered S1P level was accompanied by an increase in the expression of gene(s) for S1P-degrading enzyme(s) PLPP3 (and SGPL1). This suggests that the upregulation of the degradation process of S1P may contribute to the lowered S1P content in the corpus callosum of patients with schizophrenia. The corpus callosum contained approximately 9 times more S1P than the BA8 (Figures 1B and 1C), suggesting it is susceptible to an altered S1P metabolism.

Although schizophrenia and bipolar disorder share a genetic basis, a previous study revealed lower fatty acids levels from the skin in patients with schizophrenia, but not in those with bipolar disorder.[40] Our findings support the possibility that schizophrenia may differ from major depressive disorder and bipolar disorder with regard to biomolecular events and lowered S1P content. Lowered S1P content is involved in neuroinflammation,[41] reduction of white matter,[4] impairment of the blood-brain barrier,[42] and dysregulation of autophagy,[43] which are observed in schizophrenia.

The brain contains the highest concentration of S1P in the body.[44] Double-knockout mice of Sphk1/Sphk2, whose gene products are necessary for S1P synthesis in the brain, displayed a drastic reduction of S1P content, embryonic lethality, and severe neurogenesis defects.[45–47] This indicates S1P plays a crucial role in brain development and neural function. Furthermore, the differentiation of oligodendrocytes from induced pluripotent stem cells was impaired in patients with schizophrenia.[48] Thus, lower S1P content in the corpus callosum may contribute to white-matter abnormalities reported in patients with schizophrenia. In relation to our findings, a previous clinical study reported lower levels of plasma S1P in patients with schizophrenia without drug intake.[49]

S1P also acts as an intracellular inhibitor of histone-deacetylase (HDAC) 1 and 2.[50] Higher expression of HDAC1/HDAC2 (Hdac2) was reported in patients with schizophrenia and schizophrenia model rats.[51–54] Furthermore, mice overexpressing Hdac1 in the prefrontal cortex displayed working-memory impairment.[53,55] Therefore, lowered S1P levels may contribute to schizophrenia pathophysiology through the upregulation of HDAC1 and HDAC2 activities.

We found elevated levels of Cer and doxmeCer in the BA8. A previous study reported a higher Cer level in the prefrontal cortex of patients with schizophrenia,[56] which is consistent with our results. Ceramide is a fatty-acid-acylated form of sphingolipid, while S1P is a base form. A differential metabolism for base forms and fatty-acid-acylated forms of sphingolipids, depending on brain region, has been reported.[57] Therefore, a higher level of Cer in the BA8 may also contribute to schizophrenia pathophysiology, eg, through apoptotic dysregulation.[58,59]

There were several limitations to our study: (1) it remains elusive whether reduced S1P content is the primary cause and the upregulation of S1P receptor(s) is its consequence or vice versa; (2) if reduced S1P content is the primary event, the upstream mechanism remains to be delineated from genetic and epigenetic changes of genes for S1P metabolism; and (3) our gene-expression data were not corrected for multiple comparisons. Further studies using larger samples are required to validate our findings.

We have provided evidence suggesting an altered S1P-mediated signaling pathway elicited by lower S1P content may underlie the "myelin pathology" of a schizophrenia subset. Given that multiple agents have been developed against S1P receptors,[60] our findings support a rationale that S1P receptors should be considered as a novel therapeutic target for schizophrenia. Further studies are warranted to elucidate the detailed mechanistic role of S1P and the cause of quantitative S1P changes in patients with schizophrenia.