Article abstract
Nature Genetics 41, 688 - 695 (2009)
Published online: 24 May 2009 | doi:10.1038/ng.344
Usp46 is a quantitative trait gene regulating mouse immobile behavior in the tail suspension and forced swimming tests
Shigeru Tomida1, Takayoshi Mamiya2, Hirotake Sakamaki1, Masami Miura3, Toshihiko Aosaki3, Masao Masuda3, Minae Niwa2, Tsutomu Kameyama4, Junya Kobayashi1, Yuka Iwaki1, Saki Imai1, Akira Ishikawa5, Kuniya Abe6, Takashi Yoshimura1, Toshitaka Nabeshima2 & Shizufumi Ebihara1
Abstract
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.
- Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan.
- Department of Chemical Pharmacology, Faculty of Pharmacy, Meijo University, Tempaku-ku, Nagoya, Japan.
- Neural Circuits Dynamics Research Group, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
- Japan Institute of Psychopharmacology, Higashi-ku, Nagoya, Japan.
- Division of Applied Genetics and Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan.
- RIKEN BioResource Center, Technology and Development Team for Mammalian Cellular Dynamics, Tsukuba, Japan.
Correspondence to: Shizufumi Ebihara1 e-mail: ebihara@agr.nagoya-u.ac.jp
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