Ubiquitin-specific peptidase 46 (Usp46) regulates mouse immobile behavior in the tail suspension test through the GABAergic system.
Ubiquitin-specific peptidase 46 (Usp46) regulates mouse immobile behavior in the tail suspension test through the GABAergic system.
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DOI：
10.1371/journal.pone.0039084
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ebihara S
中科院分区：
文献类型：
--
作者：
Imai S;Mamiya T;Tsukada A;Sakai Y;Mouri A;Nabeshima T;Ebihara S
悬尾试验（TST）被广泛认为是评估抗抑郁活性和抑郁样行为的有用实验范式。我们以前已经确定了泛素特异性肽酶46（Usp 46）作为一个数量性状基因负责减少不动时间在TST小鼠。该Usp 46突变在开放阅读框中具有编码赖氨酸的3-bp缺失，并且我们表明Usp 46与GABA能系统的调节有关。然而，不动行为是如何被GABA能系统调节的还不清楚。因此，在本研究中，我们使用3-bp缺失（Usp 46突变体）和缺失Usp 46（Usp 46 KO）小鼠，研究了不动时间是否受影响GABAA受体介导的作用的药物的影响。硝西泮是GABAA受体苯二氮卓结合位点的激动剂，可增强GABA的作用，在Usp 46突变小鼠中产生TST不动时间的剂量依赖性增加，而不影响一般行为。Usp 46 KO小鼠表现出与Usp 46突变小鼠相当的短不动时间，这也通过硝西泮给药而增加。氟马西尼可拮抗硝西泮对Usp 46突变小鼠和KO小鼠的作用。这些结果表明，3bp缺失的Usp 46突变导致功能丧失表型，并且GABAA受体可能参与TST不动时间的调节。
The tail suspension test (TST) is widely recognized as a useful experimental paradigm for assessing antidepressant activity and depression-like behavior. We have previously identified ubiquitin-specific peptidase 46 (Usp46) as a quantitative trait gene responsible for decreasing immobility time in the TST in mice. This Usp46 mutation has a 3-bp deletion coding for lysine in the open reading frame, and we indicated that Usp46 is implicated in the regulation of the GABAergic system. However, it is not known precisely how the immobile behavior is regulated by the GABAergic system. Therefore, in the present study, we examined whether the immobility time is influenced by drugs affecting the action mediated by GABAA receptor using both 3-bp deleted (the Usp46 mutant) and null Usp46 (Usp46 KO) mice. Nitrazepam, an agonist at the benzodiazepine-binding site of the GABAA receptor, which potentiates the action of GABA, produced a dose-dependent increase in TST immobility time in the Usp46 mutant mice without affecting general behaviors. The Usp46 KO mice exhibited short immobility times comparable to the Usp46 mutant mice, which was also increased by nitrazepam administration. The effects of nitrazepam in the Usp46 mutant and KO mice were antagonized by flumazenil. These results indicate that the 3-bp deleted Usp46 mutation causes a loss-of-function phenotype, and that the GABAA receptor might participate in the regulation of TST immobility time.
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