Behavioral Characteristics of Ubiquitin-Specific Peptidase 46-Deficient Mice

Abstract

We have previously identified Usp46, which encodes for ubiquitin-specific peptidase 46, as a quantitative trait gene affecting the immobility time of mice in the tail suspension test (TST) and forced swimming test. The mutation that we identified was a 3-bp deletion coding for lysine (Lys 92), and mice with this mutation (MT mice), as well as Usp46 KO mice exhibited shorter TST immobility times. Behavioral pharmacology suggests that the gamma aminobutyric acid A (GABAA) receptor is involved in regulating TST immobility time. In order to understand how far Usp46 controls behavioral phenotypes, which could be related to mental disorders in humans, we subjected Usp46 MT and KO mice to multiple behavioral tests, including the open field test, ethanol preference test, ethanol-induced loss of righting reflex test, sucrose preference test, novelty-suppressed feeding test, marble burying test, and novel object recognition test. Although behavioral phenotypes of the Usp46 MT and KO mice were not always identical, deficiency of Usp46 significantly affected performance in all these tests. In the open field test, activity levels were lower in Usp46 KO mice than wild type (WT) or MT mice. Both MT and KO mice showed lower ethanol preference and shorter recovery times after ethanol administration. Compared to WT mice, Usp46 MT and KO mice exhibited decreased sucrose preference, took longer latency periods to bite pellets, and buried more marbles in the sucrose preference test, novelty-suppressed feeding test, and marble burying test, respectively. In the novel object recognition test, neither MT nor KO mice showed an increase in exploration of a new object 24 hours after training. These findings indicate that Usp46 regulates a wide range of behavioral phenotypes that might be related to human mental disorders and provides insight into the function of USP46 deubiquitinating enzyme in the neural system.

Whole Brain and Brain Regional Coexpression Network Interactions Associated with Predisposition to Alcohol Consumption

“…Our network analysis is carried out on brains of ethanol-naive animals, and thus, generates insight into the systems that are associated with the predisposition to consume alcohol. The mutation or knockout of one protein associated with these systems, ubiquitin-specific peptidase 46 (Usp 46), has very recently been demonstrated to reduce ethanol preference in mice [87]. This study validates the involvement of the system related to protein processing and protein degradation as an in vivo modulator of the phenotype of alcohol consumption.…”

A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme

“…Due to these important functions, USP1 is considered a major possible drug target (Liang et al, 2014). USP46 plays important roles in neurobiology, as a small deletion mutation in USP46 leads to neurological effects in mice, including anxiety and changes in learning and memory (Imai et al, 2013, Zhang et al, 2011). The molecular basis for these effects is not yet clear.…”

Possible Association of Polymorphisms in Ubiquitin Specific Peptidase 46 Gene with Post-Traumatic Stress Disorder

“…In addition, the Combat Exposure Scale (CES), a self-reporting scale, was administered for measuring the level of wartime traumatic stressors experienced by the combatants [30]. The total CES scores were divided into ve categories of combat exposure: light (1-8), lightmoderate (9-16), moderate (17)(18)(19)(20)(21)(22)(23)(24), moderate-heavy (25)(26)(27)(28)(29)(30)(31)(32), and heavy (33)(34)(35)(36)(37)(38)(39)(40)(41). The Alcohol Use Disorders Identi cation Test (AUDIT) was also used to assess hazardous and harmful alcohol use [31].…”

“…In animal studies, USP46 has been implicated in regulating the GABAergic system and Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamatergic system, which are important for inter-neuronal communication and higher brain functions such as learning and memory [21][22][23][24]. Notably, Ebihara and colleagues reported that Usp46 knockout mice display shortened immobility times in the tail suspension test [24] and long-term memory de cits in the object recognition test [25]. Furthermore, in humans, a genetic association between a haplotype of USP46 and major depression was reported in a Japanese population [26].…”