The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression.
The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression.
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DOI：
10.1016/j.neuropharm.2016.03.012
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发表时间：
2016-08
影响因子：
4.7
通讯作者：
Cardinaux JR
中科院分区：
文献类型：
--
作者：
Meylan EM;Halfon O;Magistretti PJ;Cardinaux JR
重度抑郁症是一种高度复杂的致残性精神疾病，影响着全世界数百万人。尽管有几种类型的抗抑郁药，但相当大比例的患者对这些药物没有反应。因此，迫切需要更好地了解抑郁症的神经生物学和抗抑郁反应的机制。我们之前报道过，缺乏creb调控的转录共激活因子1 （CRTC1）的小鼠表现出抑郁样表型，对选择性5 -羟色胺再摄取抑制剂氟西汀的抗抑郁反应减弱。在这项研究中，我们同样表明，在行为绝望范式中，Crtc1 - / -小鼠对慢性地西帕明的抗抑郁作用具有抗性。我们发现地西帕明并没有显著增加Crtc1 - / -小鼠海马和前额叶皮层中Bdnf和Nr4a1-3的表达，这支持了对这种三环抗抑郁药的钝化反应。神经可塑性基因表达的表观遗传调控与抑郁症和抗抑郁反应有关，组蛋白去乙酰化酶（HDAC）抑制剂已被证明具有抗抑郁样特性。在这里，我们表明，与传统的抗抑郁药不同，慢性全身给药HDAC抑制剂SAHA部分地挽救了Crtc1 - / -小鼠的抑郁样行为。在这些小鼠的前额叶皮层中，这种行为效应伴随着Bdnf表达的增加，而不是Nr4a1-3的表达，这表明这种表观遗传干预通过作用于CRTC1下游来恢复一组基因的表达。这些发现表明，CRTC1的改变可能与难治性抑郁症有关，并支持了一种有趣的可能性，即靶向hdac可能是抗抑郁药开发中有用的治疗策略。
Major depression is a highly complex disabling psychiatric disorder affecting millions of people worldwide. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these medications. A better understanding of the neurobiology of depression and the mechanisms underlying antidepressant response is thus critically needed. We previously reported that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) exhibit a depressive-like phenotype and a blunted antidepressant response to the selective serotonin reuptake inhibitor fluoxetine. In this study, we similarly show that Crtc1‒/‒ mice are resistant to the antidepressant effect of chronic desipramine in a behavioral despair paradigm. Supporting the blunted response to this tricyclic antidepressant, we found that desipramine does not significantly increase the expression of Bdnf and Nr4a1-3 in the hippocampus and prefrontal cortex of Crtc1‒/‒ mice. Epigenetic regulation of neuroplasticity gene expression has been associated with depression and antidepressant response, and histone deacetylase (HDAC) inhibitors have been shown to have antidepressant-like properties. Here, we show that unlike conventional antidepressants, chronic systemic administration of the HDAC inhibitor SAHA partially rescues the depressive-like behavior of Crtc1‒/‒ mice. This behavioral effect is accompanied by an increased expression of Bdnf, but not Nr4a1-3, in the prefrontal cortex of these mice, suggesting that this epigenetic intervention restores the expression of a subset of genes by acting downstream of CRTC1. These findings suggest that CRTC1 alterations may be associated with treatment-resistant depression, and support the interesting possibility that targeting HDACs may be a useful therapeutic strategy in antidepressant development.
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DOI：
10.1523/jneurosci.1758-09.2009
发表时间：
2009-09-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Covington HE 3rd;Maze I;LaPlant QC;Vialou VF;Ohnishi YN;Berton O;Fass DM;Renthal W;Rush AJ 3rd;Wu EY;Ghose S;Krishnan V;Russo SJ;Tamminga C;Haggarty SJ;Nestler EJ
通讯作者：
Nestler EJ
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.5
作者：
Marmigère, F;Givalois, L;Tapia-Arancibia, L
通讯作者：
Tapia-Arancibia, L
影响因子：
--
作者：
Kessler, RC;Berglund, P;Walters, EE
通讯作者：
Walters, EE
影响因子：
10.6
作者：
Chen, ACH;Shirayama, Y;Duman, RS
通讯作者：
Duman, RS