The tail suspension test (TST) and forced swimming test (FST) are widely used for assessing antidepressant activity and depression-like behavior. We found that CS mice show negligible immobility in inescapable situations. Quantitative trait locus (QTL) mapping using CS and C57BL/6J mice revealed significant QTLs on chromosomes 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on chromosome 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 were significantly decreased in the Usp46 mutant mice compared to control mice. These phenotypes were rescued in transgenic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects the immobility in the TST and FST, and it is implicated in the regulation of GABA action.

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CS mice exhibit several distinct phenotypes of circadian behavioral rhythms and sleep properties. Because many mental illnesses are associated with abnormalities in the circadian rhythms and sleep pattern, we characterized the behavioral phenotypes in CS mice with a battery of behavioral tests. Among these phenotypes, we found that CS mice exhibit an extremely low immobility time in both the tail suspension test (TST) and forced swimming test (FST). To uncover the genetic basis for lower immobility time, we first performed quantitative trait locus (QTL) mapping using CS and C57BL/6J mice, which 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 Usp46 mutant mice. All these phenotypes were rescued in transgenic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects the immobility in the TST and FST, and it is implicated in the regulation of GABA action.The CS mouse is an inbred strain originally established by the hybridization of the NBC and SII strains, which are both now extinct. CS mice exhibit several distinct phenotypes of circadian rhythms and sleep properties. Although in most of the inbred strains of mice, a freerunning circadian period is shorter than 24 h under constant darkness (DD), 1 CS mice have a longer circadian period than 24 h. These unusual circadian rhythms sometime spontaneously split into two activity components and interestingly these rhythms can entrain to a