Altered Trek-1 Function in Sortilin Deficient Mice Results in Decreased Depressive-Like Behavior.
Altered Trek-1 Function in Sortilin Deficient Mice Results in Decreased Depressive-Like Behavior.
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DOI：
10.3389/fphar.2018.00863
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发表时间：
2018
影响因子：
5.6
通讯作者：
Mazella J
中科院分区：
文献类型：
--
作者：
Moreno S;Devader CM;Pietri M;Borsotto M;Heurteaux C;Mazella J
背景钾通道 TREK-1 已被证明是抑郁症治疗的有效靶点。事实上，在小鼠中删除该通道会导致抑郁症抵抗表型。 TREK-1 与分选蛋白 sortilin 的关联促使我们研究从编码分选蛋白 (Sort1−/−) 的基因中删除的小鼠的行为。为了表征 sortilin 缺失对 TREK-1 活性的影响，我们结合了体内和体外的行为学、电生理学和生化方法。对 Sort1−/− 小鼠的分析显示，它们表现出：（1）不依赖皮质酮的焦虑样行为，（2）多项行为测试所证明的对抑郁的抵抗力，以及（3）中缝背核神经元的活动增加。所有这些特性都与 TREK-1 作用缺陷相关，从而导致其细胞表面表达的减少及其电生理活性的改变。通过激活弗林蛋白酶依赖性组成途径而增加的 BDNF 表达以及激活的 BDNF 受体 TrkB 的增加与 Sort1−/− 小鼠抑郁样行为的减少一致。我们的结果表明，在没有分拣蛋白的情况下，TREK-1 的表达和功能会发生改变，证实了该通道在情绪调节中的重要性，是治疗抑郁症的关键目标。
The background potassium channel TREK-1 has been shown to be a potent target for depression treatment. Indeed, deletion of this channel in mice resulted in a depression resistant phenotype. The association of TREK-1 with the sorting protein sortilin prompted us to investigate the behavior of mice deleted from the gene encoding sortilin (Sort1−/−). To characterize the consequences of sortilin deletion on TREK-1 activity, we combined behavioral, electrophysiological and biochemical approaches performed in vivo and in vitro. Analyses of Sort1−/− mice revealed that they display: (1) a corticosterone-independent anxiety-like behavior, (2) a resistance to depression as demonstrated by several behavioral tests, and (3) an increased activity of dorsal raphe nucleus neurons. All these properties were associated with TREK-1 action deficiency consequently to a decrease of its cell surface expression and to the modification of its electrophysiological activity. An increase of BDNF expression through activation of the furin-dependent constitutive pathway as well as an increase of the activated BDNF receptor TrkB were in agreement with the decrease of depressive-like behavior of Sort1−/− mice. Our results demonstrate that the TREK-1 expression and function are altered in the absence of sortilin confirming the importance of this channel in the regulation on the mood as a crucial target to treat depression.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
29
作者：
Kjolby, Mads;Andersen, Olav M.;Nykjaer, Anders
通讯作者：
Nykjaer, Anders
影响因子：
29.4
作者：
Martin, S;Navarro, V;Mazella, J
通讯作者：
Mazella, J
影响因子：
5.3
作者：
Chen, ZY;Ieraci, A;Lee, FS
通讯作者：
Lee, FS
影响因子：
16.2
作者：
Hu, Fenghua;Padukkavidana, Thihan;Vaegter, Christian B.;Brady, Owen A.;Zheng, Yanqiu;Mackenzie, Ian R.;Feldman, Howard H.;Nykjaer, Anders;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.