An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors.
An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors.
复制标题
DOI：
10.1038/mp.2013.12
复制
发表时间：
2014-03
影响因子：
11
通讯作者：
McClung, C. A.
中科院分区：
文献类型：
--
作者：
Arey, R. N.;Enwright, J. F., III;Spencer, S. M.;Falcon, E.;Ozburn, A. R.;Ghose, S.;Tamminga, C.;McClung, C. A.
具有Clock基因突变的小鼠（ClockΔ19）已被确定为躁狂症模型，然而，这种表型的机制以及锂对这些小鼠有效性所必需的大脑变化仍不清楚。在这里，我们发现胆固醇激肽（Cck）是CLOCK的直接转录靶点，并且在ClockΔ19小鼠的腹侧被盖区（VTA）中Cck的水平降低。在野生型小鼠的VTA中通过RNA干扰（RNAi）选择性敲低Cck表达产生躁狂样表型。此外，用锂的慢性治疗使Cck表达恢复到接近野生型，并且这种增加对于锂的治疗作用是必要的。ClockΔ19小鼠中Cck表达的减少似乎是由于缺乏与组蛋白甲基转移酶MLL1的相互作用，导致组蛋白H3K4me3和基因转录减少，锂逆转了这种效应。来自双相情感障碍受试者的人死后组织显示，在情绪稳定剂治疗的情况下，VTA中的Cck表达也有类似的增加。这些研究确定了Cck在躁狂症的发展和治疗中的关键作用，并描述了锂可能作为有效抗躁狂剂的一些分子机制。
Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania, however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium’s effectiveness on these mice remain unclear. Here we find that Cholecystokinin(Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knock-down of Cck expression via RNA interference (RNAi) in the VTA of wild type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective anti-manic agent.
登录
查看更多内容
DOI：
10.1080/00207450802330702
发表时间：
2008-11
期刊：
The International journal of neuroscience
影响因子：
--
作者：
Ghose S;Crook JM;Bartus CL;Sherman TG;Herman MM;Hyde TM;Kleinman JE;Akil M
通讯作者：
Akil M
影响因子：
2.9
作者：
MIYOSHI, R;KITO, S;NOMOTO, T
通讯作者：
NOMOTO, T
影响因子：
1.6
作者：
Moretti, Morgana;Valvassori, Samira S.;Quevedo, Joao
通讯作者：
Quevedo, Joao
DOI：
10.1111/j.1749-6632.2011.06336.x
发表时间：
2011-01-01
期刊：
ANNALS MEETING REPORTS
影响因子：
--
作者：
Kupfer, David J.;Angst, Jules;Zarate, Carlos A.
通讯作者：
Zarate, Carlos A.
影响因子：
--
作者：
Kripke DF;Nievergelt CM;Joo E;Shekhtman T;Kelsoe JR
通讯作者：
Kelsoe JR