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

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.

Identification of candidate genes for familial early-onset essential tremor

“…[61][62][63][64] Usp46 is strongly expressed in different brain regions including the cerebellum. In a Usp46 mouse mutant model, 65 defects in the GABA-ergic system were identified with a marked reduction in GAD67 expression. Because GAD67 catalyzes the decarboxylation of glutamate to GABA, Usp46 has been proposed to be involved in GABA synthesis.…”

“…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.…”

MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation

“…Studies have also shown that the expression of the UPS-related gene is disturbed in patients with mood disorders, including depression (Ryan et al, 2006;Gormanns et al, 2011). Although UPS has been found to play a critical role in synaptic trafficking (Wheeler et al, 2002;Yao et al, 2007) and affect behavioral despair (Tomida et al, 2009), little is known about the molecule that plays a role in creating a depressive state by modulating the UPS.…”

“…The tail suspension test was performed according to the method outlined in previous reports (Thierry et al, 1984;Tomida et al, 2009) with a minor modification. The mice were suspended by their tails using a string attached to the tails with adhesive tape (ϳ1 cm from the tip of the tail), and the string was hooked on a horizontal rod.…”

Deubiquitylases From Genes to Organism

“…USP46 has been further linked to GABAergic transmission in mouse models. 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).…”