Ubiquitin-Specific Peptidase 46 (Usp46) Regulates Mouse Immobile Behavior in the Tail Suspension Test through the GABAergic System

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 the Usp46 mutant mice, which was also increased by nitrazepam administration. The effects of nitrazepam in the Usp46 mutant and KO mice were antagonized by flumazenil. These results indicate that the 3-bp deleted Usp46 mutation causes a loss-of-function phenotype, and that the GABAA receptor might participate in the regulation of TST immobility time.

Identification of candidate genes for familial early-onset essential tremor

“…Thus, it is likely that Usp46 extensively affects the GABA-ergic system and controls a broad range of behavioral phenotypes. 65,66 One of the strengths of the study is the use of diagnostic criteria that are both reliable and valid, and that were designed specifically for genetic studies of ET, the Washington Heights Inwood Genetic Study of ET. All diagnoses were assigned by a senior movement disorder neurologist based on a detailed, videotaped neurological examination that contained a rigorous assessment of tremor and tremor phenomenology.…”

Deubiquitylases From Genes to Organism

“…Quantitative trait locus analysis of CS mice, which exhibit depressive behavior mapped to a 3-bp in-frame deletion of USP46, which reduces catalytic activity (256). Depressive behavioral effects have since been recapitulated in USP46 knockout mice, which can be alleviated by Nitazepam, which enhances GABA binding to receptors (103).…”

The WD40-repeat Proteins WDR-20 and WDR-48 Bind and Activate the Deubiquitinating Enzyme USP-46 to Promote the Abundance of the Glutamate Receptor GLR-1 in the Ventral Nerve Cord of Caenorhabditis elegans

“…USP12 and USP46 also deubiquitinate histones H2A and H2B to regulate development in Xenopus embryos (22). Although the role of USP46 in regulating GluRs has not been examined in the mammalian nervous system, usp46 mutant mice exhibit antidepressive-like behaviors and abnormalities in the GABA signaling system (28,29). However, the mechanism by which USP46 affects the GABA system is not yet known.…”