2015年4月23日
Inhibition of histone deacetylases enhances the function of serotoninergic neurons in organotypic raphe slice cultures.
Neuroscience letters
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- 巻
- 593
- 号
- 開始ページ
- 72
- 終了ページ
- 7
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.neulet.2015.03.028
- 出版者・発行元
- ELSEVIER IRELAND LTD
Inhibition of histone deacetylases (HDACs) is a promising approach for the treatment of mood disorders. However, the effects of HDAC inhibition on the serotonin (5-HT) system, a common target for psychiatric disorders, are poorly understood. Here, we show that a broad-spectrum HDAC inhibitor, trichostatin A (TSA), enhances the function of 5-HT neurons in organotypic raphe slice cultures. Sustained treatment with TSA (1μM) for 2 or 4 days significantly increased the 5-HT tissue content and tryptophan hydroxylase 2 (TPH2) expression, which were accompanied by hyper-acetylation of histone H3 in the promoter region of the TPH2 gene. TSA treatment for 4 days increased the extracellular 5-HT level, which was significantly suppressed in the presence of the selective AMPA receptor (AMPAR) antagonist NBQX. Moreover, the expression of both the AMPAR subunit GluA2 and Ca(2+)/calmodulin-dependent kinase II α (CaMKIIα) mRNAs were significantly increased by TSA treatment. Co-treatment with the CaMKII inhibitors KN-62 and KN-93 prevented the TSA-induced increase in 5-HT release, but had no effect on the increases in 5-HT tissue content. These results suggest that inhibition of HDACs increases 5-HT synthesis and release by epigenetic mechanisms, and that 5-HT release is mediated by the enhancement of AMPAR-mediated excitatory inputs and CaMKII signaling.
- リンク情報
- ID情報
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- DOI : 10.1016/j.neulet.2015.03.028
- ISSN : 0304-3940
- eISSN : 1872-7972
- PubMed ID : 25796177
- Web of Science ID : WOS:000353604700014