Abstract
Epigenetic alterations and impaired oligodendroglial myelination in the prefrontal cortex have been shown to correlate with behavioral and cognitive dysfunctions in social deprivation. Our previous study demonstrated that quetiapine, an atypical antipsychotic, could promote oligodendroglial differentiation and myelination. However, whether and how quetiapine could be beneficial in modulating aberrant epigenetic alterations in oligodendroglial cells and relieving behavioral alterations from social isolation is unknown. In this study, quetiapine was orally administered in adolescent mice undergoing mild stress of social isolation. We firstly confirmed that social isolation during a novel adolescent period could impair sociability, but not locomotive behaviors in mice. Moreover, quetiapine alleviated myelin deficits, and increased levels of histone methylation (H3K9me3) in mature oligodendroglia in the prefrontal cortex of socially isolated mice. Strikingly, quetiapine treatment significantly increased locomotive activity, and successfully reversed social avoidance behavior of the socially isolated mice. Taken together, our data suggest that quetiapine may rescue behavioral changes from social isolation through modulating epigenetic status toward the beneficial direction for oligodendroglial maturation, providing new insights into the pharmacological mechanism of quetiapine for mental illnesses.
Highlights
Social deprivation, that could induce mild cognitive impairment, impulsivity and social deficits [1, 2], has been well-recognized as an environmental risk factor of psychiatric disorders [3]
We employed a mouse model through social isolation, which can led to myelin deficits in the prefrontalQuetiapine Restores Oligodendroglia and Behaviors cortex (PFC) and impair the sociability of mice
We found that quetiapine can modulate the status of histone methylation in OLs, and rescue myelin deficiency in the PFC of the adult mice subjected to social isolation
Summary
That could induce mild cognitive impairment, impulsivity and social deficits [1, 2], has been well-recognized as an environmental risk factor of psychiatric disorders [3]. Multiple environmental risk factors have been identified to induce abnormal epigenetic alterations in the brains of schizophrenia cohorts [10], including DNA methylation, histone modification, and dysregulation of miRNAs [11]. The transition from OL progenitor cells to mature OLs is characterized by a rapid and substantial chromatin remodeling, which is highly governed by epigenetic regulators including histone modification and DNA methylation factors [7, 14, 15]. Some rodent studies demonstrated that social isolation could result in aberrant histone methylation changes in OLs [7]. While clemastine reversed histone methylation in OLs, promote myelination in the PFC and rescued behavioral changes of social isolation [16], raising an intriguing possibility that epigenetic status of OLs could be a novel target for drug treatment
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