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Ubiquitin-specific peptidase 46 (Usp46) regulates mouse immobile behavior in the tail suspension test through the GABAergic system.

Imai S, Mamiya T, Tsukada A, Sakai Y, Mouri A, Nabeshima T, Ebihara S - PLoS ONE (2012)

Bottom Line: 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.These results indicate that the 3-bp deleted Usp46 mutation causes a loss-of-function phenotype, and that the GABA(A) receptor might participate in the regulation of TST immobility time.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.

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 GABA(A) receptor using both 3-bp deleted (the Usp46 mutant) and Usp46 (Usp46 KO) mice. Nitrazepam, an agonist at the benzodiazepine-binding site of the GABA(A) 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 GABA(A) receptor might participate in the regulation of TST immobility time.

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Effects of nitrazepam administration on tail suspension test (TST) immobility time.Nitrazepam induces dose-dependent increases of TST immobility time in Usp46 mutant mice (MT). Data are expressed as mean + S.E.M. for 6 mice in each group. ##P<0.01 compared with the wild-type mice for each dose; *P<0.05, **P<0.01 (two-way ANOVA with Bonferroni’s test).
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pone-0039084-g003: Effects of nitrazepam administration on tail suspension test (TST) immobility time.Nitrazepam induces dose-dependent increases of TST immobility time in Usp46 mutant mice (MT). Data are expressed as mean + S.E.M. for 6 mice in each group. ##P<0.01 compared with the wild-type mice for each dose; *P<0.05, **P<0.01 (two-way ANOVA with Bonferroni’s test).

Mentions: Nitrazepam, an agonist of the benzodiazepine-binding site of GABAA receptors that causes an enhanced binding of GABA to these receptors, produced a dose-dependent increase in TST immobility times in the Usp46 mutant mice (Fdose (3,40) = 19.09, P<0.01; Fgenotype(1,40) = 73.56, P<0.01; Fdose×genotype(3,40) = 5.36, P<0.01; two-way ANOVA) (Fig. 3). However, such a dose-dependent increase was not apparent in the wild-type mice, although a significant difference between doses of 0.1 mg/kg and 1 mg/kg was observed. Because nitrazepam is known to have sedative effects, we measured general behaviors in OFT. However, an administration of this drug did not affect general behaviors (total activity, frequency of climbing + rearing, and grooming for 5 min in OFT) (P>0.05; one-way ANOVA with Tukey-Kramer post-hoc test) (Table 1), while nitrazepam affected TST immobility times in the Usp46 mutant mice.


Ubiquitin-specific peptidase 46 (Usp46) regulates mouse immobile behavior in the tail suspension test through the GABAergic system.

Imai S, Mamiya T, Tsukada A, Sakai Y, Mouri A, Nabeshima T, Ebihara S - PLoS ONE (2012)

Effects of nitrazepam administration on tail suspension test (TST) immobility time.Nitrazepam induces dose-dependent increases of TST immobility time in Usp46 mutant mice (MT). Data are expressed as mean + S.E.M. for 6 mice in each group. ##P<0.01 compared with the wild-type mice for each dose; *P<0.05, **P<0.01 (two-way ANOVA with Bonferroni’s test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375232&req=5

pone-0039084-g003: Effects of nitrazepam administration on tail suspension test (TST) immobility time.Nitrazepam induces dose-dependent increases of TST immobility time in Usp46 mutant mice (MT). Data are expressed as mean + S.E.M. for 6 mice in each group. ##P<0.01 compared with the wild-type mice for each dose; *P<0.05, **P<0.01 (two-way ANOVA with Bonferroni’s test).
Mentions: Nitrazepam, an agonist of the benzodiazepine-binding site of GABAA receptors that causes an enhanced binding of GABA to these receptors, produced a dose-dependent increase in TST immobility times in the Usp46 mutant mice (Fdose (3,40) = 19.09, P<0.01; Fgenotype(1,40) = 73.56, P<0.01; Fdose×genotype(3,40) = 5.36, P<0.01; two-way ANOVA) (Fig. 3). However, such a dose-dependent increase was not apparent in the wild-type mice, although a significant difference between doses of 0.1 mg/kg and 1 mg/kg was observed. Because nitrazepam is known to have sedative effects, we measured general behaviors in OFT. However, an administration of this drug did not affect general behaviors (total activity, frequency of climbing + rearing, and grooming for 5 min in OFT) (P>0.05; one-way ANOVA with Tukey-Kramer post-hoc test) (Table 1), while nitrazepam affected TST immobility times in the Usp46 mutant mice.

Bottom Line: 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.These results indicate that the 3-bp deleted Usp46 mutation causes a loss-of-function phenotype, and that the GABA(A) receptor might participate in the regulation of TST immobility time.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.

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 GABA(A) receptor using both 3-bp deleted (the Usp46 mutant) and Usp46 (Usp46 KO) mice. Nitrazepam, an agonist at the benzodiazepine-binding site of the GABA(A) 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 GABA(A) receptor might participate in the regulation of TST immobility time.

Show MeSH