マウスの"行動的絶望"を制御する遺伝子の特定
マウスの"行動的絶望"を制御する遺伝子の特定
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发表时间：
2010-02
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通讯作者：
S. Ebihara;Shigeru Tomida
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作者：
S. Ebihara;Shigeru Tomida
我们发现CS小鼠在悬尾试验（TST）和强迫游泳试验（FST）中均表现出极低的静止时间（几乎没有静止）。在这些试验中，动物受到短期的、不可避免的压力，比如被尾巴悬吊起来，或者被迫在一个装满水的圆柱体中游泳。在这种情况下，动物迅速采取一种典型的一动不动的姿势，这种姿势被称为“行为绝望”，因为它们认为动物已经放弃了逃跑的希望。这些测试已被广泛用于评估抗抑郁药物的活性和抑郁样行为。利用CS和C57BL/6J小鼠进行数量性状位点（QTL）定位，在4号染色体（FST）和5号染色体（TST和FST）上发现了显著的QTL。为了鉴定Chr 5上的数量性状基因，我们利用几个同源和亚同源菌株将QTL区间缩小到0.5 Mb。具有赖氨酸密码子缺失的泛素特异性肽酶46 （Usp46）位于该区域。这种缺失影响了筑巢、肌醇诱导的翻正反射和丙咪嗪的抗静止作用。与对照小鼠相比，Usp46突变小鼠海马CA1锥体神经元的肌醇诱导电流和海马67-kDa谷氨酸脱羧酶异构体的表达显著降低。所有这些表型在含有野生型Usp46的细菌人工染色体的转基因小鼠中被恢复。因此，Usp46影响“行为绝望”，并与GABA作用的调节有关。
We found that CS mice exhibit an extremely low immobility time (almost no immobility) in both the tail suspension test (TST) and forced swimming test (FST). In these tests, animals are subjected to the short-term, inescapable stress of being suspended by their tail or being forced to swim in a water-filled cylinder. In such situations, the animals rapidly adopt a characteristic immobile posture that has been named "behavioral despair" on the assumption that the animals have given up hope of escaping. These tests have been widely used for assessing antidepressant activity and depression-like behavior. Quantitative trait locus (QTL) mapping using CS and C57BL/6J mice revealed significant QTLs on chromosomes (Chrs) 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on Chr 5, we narrowed the QTL interval to 0.5 Mb using several congenic and subcongenic strains. Ubiquitin-specific peptidase 46 (Usp46) with a lysine codon deletion was located in this region. This deletion affected nest-building, muscimol-induced righting reflex and anti-immobility effects of imipramine. The muscimol-induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase significantly decreased in the Usp46 mutant mice compared to control mice. All these phenotypes were rescued in transgenic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects "behavioral despair" and it is implicated in the regulation of GABA action.