Usp46 is a quantitative trait gene regulating mouse immobile behavior in the tail suspension and forced swimming tests

• Published in: Nature genetics Vol. 41; no. 6; pp. 688 - 695
• Main Authors: Abe, Kuniya, Kobayashi, Junya, Kameyama, Tsutomu, Yoshimura, Takashi, Niwa, Minae, Mamiya, Takayoshi, Masuda, Masao, Imai, Saki, Ebihara, Shizufumi, Sakamaki, Hirotake, Aosaki, Toshihiko, Ishikawa, Akira, Nabeshima, Toshitaka, Iwaki, Yuka, Miura, Masami, Tomida, Shigeru
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2009; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animal locomotion; Animals; Behavior; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosome Mapping; Chromosomes; Codon - genetics; College students; Colleges & universities; Endopeptidases - genetics; Experiments; Fundamental and applied biological sciences. Psychology; gamma-Aminobutyric Acid; Gene Function; Gene mapping; Genetic aspects; Genetic Association Studies - methods; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Glutamate Decarboxylase - genetics; Human Genetics; Immobilization; Immunohistochemistry; Mice; Mice, Inbred C57BL - genetics; Mice, Inbred Strains - genetics; Neurons; Physiological aspects; Quantitative trait loci; Quantitative Trait Loci - genetics; Sequence Deletion; Swimming; Tail - anatomy & histology; Tail - physiology; Japan; Vertebrata; Mammalia; Gene; Mouse; Quantitative character; Rodentia; Exploration; Behavior
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.344

Shizufumi Ebihara and colleagues report the identification of Usp46 as a quantitative trait gene underlying mouse behavior in the tail suspension and forced swimming tests, which are widely used for assessing depression-like behavior. Usp46 encodes a ubiquitin-specific peptidase. 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.