Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 3, Pages 957-962Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3608-15.2016
Keywords
depression; epigenetics; myelination; prefrontal cortex; social isolation
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Funding
- National Institute of Neurological Disorders and Stroke [2R37NS042925-10, R01NS52738]
- National Institutes of Health (NIH)-National Institute of Neurological Disorders and Stroke Center Core Grant [5P30 NS047463]
- NIH-National Cancer Institute Cancer Center [P30 CA016059]
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Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior.
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