RESUMO
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.
Assuntos
Locos de Características Quantitativas/genética , Cauda/fisiologia , Animais , Mapeamento Cromossômico , Códon/genética , Endopeptidases/genética , Estudos de Associação Genética/métodos , Glutamato Descarboxilase/genética , Imobilização , Camundongos , Camundongos Endogâmicos C57BL/genética , Camundongos Endogâmicos/genética , Deleção de Sequência , Cauda/anatomia & histologia , Ácido gama-AminobutíricoRESUMO
In mice, genetic differences between inbred strains have been shown for several parameters of sleep and circadian activity rhythms. Our previous studies have demonstrated that CS mice have three remarkable characteristics in the circadian rhythm of locomotor activity: (1) high activity both during the day and night, (2) unstable freerunning period and (3) spontaneous rhythm splitting. In order to characterize sleep properties of CS mice, we compared circadian sleep patterns of CS with those of C57BL/6J and C3H/He mice which have normal circadian activity rhythms. Although C57BL/6J and C3H/He mice exhibited clear daily sleep-wake rhythms in the amount of each sleep parameter (Awake, SWS, PS), CS mice did not show clear rhythms in these parameters. The differences were particularly conspicuous in PS; no apparent day-night differences in the amount of PS, PS counts and PS interval (the interval between successive PS episodes) in CS mice. In addition, the ratio of PS to total sleep time was significantly larger in CS mice than other strains. Of these parameters, the most considerable was PS latency which was extremely short and direct transition from Awake to PS without appearance of SWS frequently occurred in these mice. These results indicate that CS mice may be useful for the understanding of sleep mechanisms and its dysfunction.
