Lipidomics reveals dysfunctional glycosynapses in schizophrenia and the G72/G30 transgenic mouse
Introduction
Decrements in oligodendroglial density (Hof et al., 2003, van den Heuvel and Fornito, 2014), increased numbers of abnormal oligodendroglia (Uranova et al., 2011, van den Heuvel and Fornito, 2014), decreased fractional anisotropy derived from diffusion tensor imaging of fiber tracts (Nakamura et al., 2005, Wang et al., 2014), and resting-state fMRI analyses (2005; Wang et al., 2014) have all indicated that schizophrenia is characterized by anatomical/functional dysconnectivity. Alterations in connectivity are ultimately thought to result in disruption of complex neuronal circuits involved in perception, cognition, and emotion.
At the molecular level, decreased expression of a number of oligodendrocyte genes that could alter myelin lipid composition have been reported (Voineskos et al., 2013, Roussos and Haroutunian, 2014). Since the dry mass of myelin is 70% to 85% lipid, we undertook a high-resolution shotgun lipidomic analysis of gray (GM) and white (WM) matter in postmortem frontal cortex obtained from patients suffering from schizophrenia and unaffected individuals. In addition, we utilized this analytical platform, which surveys over 700 individual lipids across 26 lipid subclasses (Wood and Shirley, 2013), to evaluate the lipid profile of the G72/G30 transgenic (G72Tg) mouse model of schizophrenia-like symptoms (Otte et al., 2009). In the search for genes that are involved in the etiology of schizophrenia, the primate specific gene locus G72/G30 has been identified (Drews et al., 2013). The gene product LG72 is a multi-functional protein with mitochondrial functions (Drews et al., 2013), and/or peroxisomal D-amino acid oxidase regulator activity (Otte et al., 2009, Drews et al., 2013). Our previous studies of G72Tg mice have demonstrated oxidative stress (Filiou et al., 2012), abnormal expression of oligodendrocyte proteins (Filiou et al., 2012), and behavioral alterations (Otte et al., 2009) that corroborate this transgenic mouse as an animal model of schizophrenia-like symptoms (Otte et al., 2009, Filiou et al., 2012).
Section snippets
Patient brain samples
Frontal cortex brain samples (BA 9; 10 controls and 10 schizophrenia) were provided by the UCLA brain bank. WM and GM were micro-dissected and validated by the PlsEtn36:2/PtdEtn 40:6 ratio (< 1 for GM and > 12 for WM). Schizophrenia patients were diagnosed based on the Structural Interview for Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). The demographics of the donors are presented in Table 1.
Animals
Both hippocampi from G72Tg (N = 11) and wild-type (WT, N = 10) male CD1 mice (8 to 10
Sphingolipids
The most remarkable finding of our lipidomic analyses was of significantly elevated sulfatides in the WM and GM in the frontal cortex of postmortem schizophrenia tissue and in the hippocampus of G72Tg mice (Fig. 1A). Galactosylceramides (GalCer), the metabolic precursors of sulfatides, also were elevated in the frontal cortex GM (Fig. 1B) and WM (Fig. 1C) of patients suffering from schizophrenia, but not in the hippocampus of G72Tg mice. There was no correlation with gender, PMI, or age;
Discussion
Structural glycerophospholipids and sphingolipids are major components of myelin and also serve as complex reservoirs of signal transduction mediators. Our observations of altered levels of sulfatides, galactosylceramides, and plasmalogens in the frontal cortex of schizophrenia subjects clearly demonstrate, at the biochemical level, that myelin is dysfunctional in schizophrenia.
GalCer and sulfatides (sulfated GalCer) are glycosphingolipids that are primarily synthesized by oligodendrocytes and
Role of funding source
The funding sources had no role in these studies.
Author contributions
PLW, MDF, and CWT contributed equally to the experimental design, conduct of experiments, data analysis, and writing of the manuscript. DMO and AZ provided G72Tg and control mouse lines. We thank Larysa Teplytska for expert technical assistance.
Competing financial interests
The authors declare no competing financial interests. The funding sources also had no role in these studies.
Acknowledgments
Frontal cortex specimens were obtained from the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Center, 11301 Wilshire Blvd. Los Angeles, CA 90073, which is sponsored by the National Institutes of Health, National Multiple Sclerosis Society, and the US Department of Veterans Affairs. This work was funded by DeBusk College of Osteopathic Medicine, Lincoln Memorial University, and by the Max Planck Society. MDF is supported by a grant from the Deutsche
References (24)
- et al.
Involvement of the primate specific gene G72 in schizophrenia: from genetic studies to pathomechanisms
Neurosci. Biobehav. Rev.
(2013) - et al.
Myelination and oxidative stress alterations in the cerebellum of the G72/G30 transgenic schizophrenia mouse model
J. Psychiatr. Res.
(2012) - et al.
Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia
Biol. Psychiatry
(2003) - et al.
Fronto-temporal disconnectivity in schizotypal personality disorder: a diffusion tensor imaging study
Biol. Psychiatry
(2005) - et al.
Behavioral changes in G72/G30 transgenic mice
Eur. Neuropsychopharmacol.
(2009) - et al.
Altered thalamic membrane phospholipids in schizophrenia: a postmortem study
Biol. Psychiatry
(2004) - et al.
Plasmalogens the neglected regulatory and scavenging lipid species
Chem. Phys. Lipids
(2011) - et al.
Disrupted resting-state functional connectivity in minimally treated chronic schizophrenia
Schizophr. Res.
(2014) - et al.
Participation of galactosylceramide and sulfatide in glycosynapses between oligodendrocyte or myelin membranes
FEBS Lett.
(2010) The role and metabolism of sulfatide in the nervous system
Mol. Neurobiol.
(2008)
Oxidative stress and schizophrenia: recent breakthroughs from an old story
Curr. Opin. Psychiatry
The glycosynapse
Proc. Natl. Acad. Sci. U. S. A.
Cited by (38)
The relationship between cannabis use, schizophrenia, and bipolar disorder: a genetically informed study
2023, The Lancet PsychiatryMeta-analysis of transcriptional regulatory networks for lipid metabolism in neural cells from schizophrenia patients based on an open-source intelligence approach
2022, Neuroscience ResearchCitation Excerpt :Examples of such abnormalities include structural alterations of lipids in the brain and skin and changes in blood plasma and serum lipids (Shimamoto-Mitsuyama et al., 2021). For instance, multiple cases of derangements of membrane phospholipids and polyunsaturated fatty acids have been reported in the brains of schizophrenia patients (Ghosh et al., 2017; Tessier et al., 2016; Wood et al., 2014; Yao et al., 2000). Other studies have shown that the composition of skin ceramides can also be affected (Smesny et al., 2013).
Homeostasis of lipid metabolism in disorders of the brain
2021, Encyclopedia of Behavioral Neuroscience: Second EditionThe impact of quetiapine on the brain lipidome in a cuprizone-induced mouse model of schizophrenia
2020, Biomedicine and PharmacotherapyOmega-3 fatty acids and mental health
2020, Global Health Journal