Abstract
Increasing evidence has demonstrated that in addition to dysfunction of neuronal circuitry, oligodendroglial dysfunction and/or disruption of white matter integrity are found in the brains of patients with schizophrenia. DNA methylation, a well-established risk factor for schizophrenia, has been demonstrated to cause neuronal dysfunction; however, whether dysregulation of DNA methylation contributes to oligodendroglial/myelin deficits in the pathogenesis of schizophrenia remains unclear. In the present study, by using L-methionine-treated mice, we confirmed that mice with DNA hypermethylation exhibited an anxious phenotype, impaired sociability, and sensorimotor gating deficits. Notably, DNA hypermethylation in oligodendroglial cells led to dysregulation of multiple oligodendroglia-specific transcription factors, which indicated disruption of the transcriptional architecture. Furthermore, DNA hypermethylation caused a reduction of oligodendroglial lineage cells and myelin integrity in the frontal white matter of mice. Taken together, these results indicate that DNA hypermethylation leads to oligodendroglial and/or myelin deficits, which may, at least in part, contribute to schizophrenia-like behaviors in mice. This study provides new insights into the possibility that precise modulation of DNA methylation status in oligodendroglia could be beneficial for the white matter pathology in schizophrenia.
Highlights
Genetic alterations contribute to the high heritability of schizophrenia (SZ), and environmental factors that lead to aberrant epigenetic modifications may exacerbate the disease through dysregulation of risk genes (Shorter and Miller, 2015)
We found that DNA hypermethylation in oligodendroglia caused a reduction of oligodendroglial lineage cells and myelin integrity, which may have partly contributed to SZ-like behaviors in L-methionine-treated mice
From the insight of brain development, the risk age of schizophrenia onset coincides with the key period of postnatal oligodendroglial differentiation and myelination (Miller et al, 2012; Lee et al, 2014), which ranges from juvenile to young adult in mice
Summary
Genetic alterations contribute to the high heritability of schizophrenia (SZ), and environmental factors that lead to aberrant epigenetic modifications may exacerbate the disease through dysregulation of risk genes (Shorter and Miller, 2015). DNA methylation, one of the most important epigenetic modifications in SZ (Montano et al, 2016; Sugawara et al, 2018), may stably integrate multiple layers of gene-environment interactions and lead to permanent alterations in brain. Dysregulation of multiple oligodendroglial-specific genes, such as Sox, PLP1, Olig, and Olig, has been found in the brains of SZ patients (Nicolay et al, 2007; Liu et al, 2015; Robinson et al, 2016), indicating that epigenetic dysregulation of candidate genes in oligodendroglia could contribute to the white matter deficits observed in SZ
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