ubiquitin-specific peptidase 46 (usp46) regulates mouse immobile behavior in the tail suspension test through the gabaergic systemubiquitin-specific肽酶46(usp46)调节小鼠尾悬挂固定行为测试通过gaba ergic系统.pdf

Ubiquitin-Specific Peptidase 46 (Usp46) Regulates Mouse Immobile Behavior in the Tail Suspension Test through the GABAergic System 1 2 3 1 2 2 Saki Imai , Takayoshi Mamiya , Akira Tsukada , Yasuyuki Sakai , Akihiro Mouri , Toshitaka Nabeshima , Shizufumi Ebihara1* 1 Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan, 2 Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan, 3 Division of Applied Genetics and Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan Abstract 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 t