期刊
EUROPEAN NEUROPSYCHOPHARMACOLOGY
卷 25, 期 11, 页码 2036-2048出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.euroneuro.2015.08.016
关键词
Chronic social defeat stress (CSDS); Histone deacetylase 5 (HDAC5); Prefrontal cortex (PFC); Sirt2; Imipramin; Major depression
资金
- Ministry of Economy and Competitiveness, Spanish Government [SAF2011-27910]
- Italian Ministry of Health [RF-2010-2318330]
- Italian FIRB [RBFR10ZJQT]
- Sapienza Ateneo Project [BLUEPRINT/282510, A-PARADDISE/ 602080]
- Asociacion de Amigos de la Universidad de Navarra
- Spanish Ministry of Economy and Competitiveness
Changes in histone acetylation could contribute to the pathogenesis of depression and antidepressant therapy. Using the chronic social defeat stress (CSDS) model of depression and different antidepressant treatments we studied the regulation of histone deacetylases (Hdac's) and synaptic plasticity markers in the prefrontal cortex (PFC). Further, functional implication of identified Hdac's in brain plasticity was explored. Mice were exposed to CSDS (10 days) followed by saline or imipramine (4 weeks). PFC Hdac's mRNA abundance was studied and compared to human's. Further, protein expression of acetylated histones (AcH3 and AcH4), neuroplasticity markers (CREB and pro-BDNF) and selected Hdac's were analyzed. Moreover, other antidepressants (fluoxetine and reboxetine) and selective HDAC inhibitors were studied. CSDS increased Hdac5 and Sirt2 mRNA whereas repeated imipramine did the opposite. Accordingly, stress and imipramine induced opposite changes on AcH3, AcH4 and CREB expression. At protein level, CSDS upregulated nuclear fraction of Hdac5 and repeated imipramine and reboxetine increased its phosphorylated form (p-Hdac5), mainly located in the cytoplasm. Moreover, Sirt2 was downregulated by all monoaminergic antidepressants. Further, repeated treatment with the class IIa Hdac inhibitor MC1568 and the Sirt2 inhibitor 33i for three weeks increased synaptic plasticity in the prefrontal cortex. Our results suggest that Hdac5 and Sirt2 upregulation could constitute stable stress-induced neuronal adaptations. Noteworthy, the SIRT2 upregulation in depressed patients supports the interest of this target for therapeutic intervention. On the other hand, cytoplasmic Hdac5 export and Sirt2 downregulation induced by monoaminergic antidepressants could contribute to the well-known beneficial effects of antidepressants on brain plasticity. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据