Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice
Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice
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DOI：
10.1523/jneurosci.3608-15.2016
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发表时间：
2016-01-20
影响因子：
5.3
通讯作者：
Casaccia, Patrizia
中科院分区：
文献类型：
--
作者：
Liu, Jia;Dupree, Jeffrey L.;Casaccia, Patrizia
髓鞘结构和少突胶质细胞功能的改变与认知和运动功能障碍以及社会行为缺陷有关。我们和其他人以前已经证明，社会隔离在小鼠诱导行为，转录和超微结构的变化，在少突胶质细胞的前额叶皮层（PFC）。然而，增强髓鞘形成和少突胶质细胞分化是否有利于逆转这种变化仍有待研究。为了验证这一假设，我们口服氯马斯汀，一种抗毒蕈碱化合物，已被证明可以增强体外少突胶质细胞分化和髓鞘形成，在社会隔离后的成年小鼠中持续2周。氯马斯汀成功逆转了长期社交隔离小鼠的社交回避行为。受损的髓鞘形成通过口服氯马斯汀治疗得以挽救，并且与增强的少突胶质细胞祖细胞分化和表观遗传变化相关。氯马斯汀诱导更高水平的抑制性组蛋白甲基化（H3K9me3），异染色质的标志物，少突胶质细胞，但不是神经元，PFC。这与氯马斯汀在培养的原代小鼠少突胶质细胞中升高H3K9组蛋白甲基转移酶活性的能力是一致的，这种作用可以通过与毒蕈碱共同处理来拮抗。我们的数据表明，促进成人髓鞘形成是逆转抑郁样社会行为的潜在策略。
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.