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TASK channels, members of the two-pore-domain potassium channel family, contribute towards the resting membrane potential and have been implicated in the mechanism of general anaesthesia. Previous work from our group with a TASK-3 channel knockout (T3KO) mouse showed a reduction in halothane sensitivity using a loss of righting reflex (LORR) assay, and absence of the theta brain oscillation induced in wild type (WT) mice by halothane anaesthesia. Two further strains of knockout mice, the TASK-1 knockout (T1KO) and the double knockout (DKO: TASK-1 and -3 channels), were compared with WT using the LORR assay, cortical electroencephalogram recording in response to halothane and during sleep. The mechanistic basis for the diminished theta oscillation in T3KO mice was investigated by recording in CA1 pyramidal cells of the hippocampus. The LORR assay revealed a decrease in halothane sensitivity in T1KO but not DKO compared with WT. The T1KO strain had a theta oscillation induced by exposure to halothane similar to that of WT mice, whereas that observed in the DKO was intermediate between WT and T3KO. T1KO differed from other strains in that the distribution of sleep and wake periods was uniform across the diurnal cycle. The resting membrane potential did not differ between strains during control or halothane exposure. During control there was no strain difference in action potential (AP). Halothane altered AP shape in WT but not the T3KO strain. WT had a greater ability to sustain AP firing than T3KO during halothane. These data show that T1KO mice have decreased anaesthetic sensitivity and altered sleep structure compared with WT, indicating a role for this channel in anaesthetic sensitivity and sleep. The similar resting membrane potential and lack of response to halothane in the T3KO makes pyramidal cells an unlikely source of the theta ablation observed.

Abstract: Chimpanzees have been previously used to study HAV infection in vivo but they are expensive and difficult to maintain and thus, there is a need for a small animal model. Our aim is to test the susceptibility of the SCID-beige/Alb-uPA mice with chimeric human/mouse livers to HAV infection. Chimeric mice were IV inoculated with HAV and HAV produced fully infectious particles within the serum and feces, by one week post-infection. eHAV circulated the blood of infected chimeric mice consistent with human infections. Due to the lack of an adaptive immune system, HAV caused a persistent infection with a lack of inflammation within the liver. Pre-exposure to neutralizing antibody was fully protective while IFN treatment was able to suppress HAV infection. This study shows that the chimeric mice are permissive to HAV infection and represent a valuable small animal model for future studies.