Phenotypic analysis of GalR2 knockout mice in anxiety- and depression-related behavioral tests
Phenotypic analysis of GalR2 knockout mice in anxiety- and depression-related behavioral tests
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DOI：
10.1016/j.npep.2008.04.009
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发表时间：
2008-08-01
期刊：
影响因子：
2.9
通讯作者：
Bartfai, Tamas
中科院分区：
文献类型：
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作者：
Lu, Xiaoying;Ross, Brendon;Bartfai, Tamas
神经肽Galanin通过三种G蛋白偶联受体亚型GalR1至GalR3调节多种中枢神经系统功能。甘丙肽及其受体在啮齿类动物大脑边缘结构中高水平表达。侧脑室注射甘丙肽已被证明可以调节大鼠的抑郁和焦虑样行为。我们以前已经证明，慢性抗抑郁药物治疗增加了GalR2偏爱配体Galanin(2-11)与大鼠中缝背核(DRN)的结合，这一发现以及DRN内注射Galanin(2-11)增加了海马区5-羟色胺的释放，表明GalR2信号可能通过调节向上的5-羟色胺能流出而发挥抗抑郁作用。最近，两个研究小组报道了他们对GalR2基因敲除(GalR2KO)小鼠的表型分析，该小鼠系通过基因捕获方法产生，保持在129S1/SvImJ遗传背景上。GalR2KO小鼠品系中唯一的阳性发现是升高的正迷宫特有的类似焦虑的表型。由于已知遗传背景会影响行为测试的结果，在本研究中，我们使用一组不同的抑郁和焦虑相关测试分析了一个单独的GalR2KO系，该系是通过靶向缺失产生的，并保持在C57BL/6背景上。GalR2KO小鼠在习得性无助范式中表现出更持久的抑郁样表型，并且在尾部悬挂试验中表现出更多的静止不动，当本研究的结果与Gottsch及其同事报道的结果结合在一起时。GalR2KO突变体在高架正迷宫、开阔场地和明暗转移测试中表现出与野生型窝种类似的焦虑行为。目前的发现与GalR2信号的抗抑郁药样作用相一致，提示GalR2可能是治疗抑郁障碍的有效药物靶点。(C)2008爱思唯尔有限公司。保留所有权利。
Neuropeptide galanin modulates a variety of central nervous system functions by signaling through three G-protein-coupled receptor subtypes, GalR1 through GalR3. Galanin and its receptors are expressed at high levels in the limbic structures of the rodent brain. Intracerebroventricular injection of galanin has been shown to modulate depression and anxiety-like behaviors in the rat. We have previously shown that chronic antidepressant treatments increase the binding of a GalR2-preferring ligand, galanin (2-11), to the dorsal raphe nucleus (DRN) of the rat, which, along with the finding that intra-DRN infusion of galanin (2-11) increases the release of serotonin in the hippocampus, suggests that GalR2 signaling might exert antidepressant-like actions by modulating ascending serotonergic outflow. Recently, two research groups reported their phenotypic analysis of a GalR2 knockout (GalR2KO) mouse line, produced by gene-trapping method and maintained on a 129S1/SvImJ genetic background. The only positive finding in that GalR2KO mouse line was an anxiogenic-like phenotype specific to the elevated plus-maze. Because it is known that genetic background can affect the outcome of behavioral tests, in the present study, we analyzed a separate GalR2KO line, which was produced by targeted deletion and maintained on a C57BL/6 background, using a different set of depression- and anxiety-related tests. GalR2KO mice exhibited a more persistent depressive-like phenotype in the learned helplessness paradigm as well as increased immobility in the tail suspension test when results from the present studies were combined by fixed effect meta-analysis with that reported by Gottsch and colleagues. GalR2KO mutants showed anxiety-like behavior comparable to wild-type littermates in the elevated plus-maze, open-field, and light-dark transfer tests. The present findings are consistent with a predicted antidepressant-like effect of GalR2 signaling, suggesting that GalR2 might be a valid drug target for depressive disorders. (C) 2008 Elsevier Ltd. All rights reserved.