K+ channel TASK-1 knockout mice show enhanced sensitivities to ataxic and hypnotic effects of GABAA receptor ligands

TASK two-pore-domain leak K+ channels occur throughout the brain. However, TASK-1 and TASK-3 knockout (KO) mice have few neurological impairments and only mildly reduced sensitivities to inhalational anesthetics, contrasting with the anticipated functions and importance of these channels. TASK-1/-3 channel expression can compensate for the absence of GABA A receptors in GABA(A) alpha 6 KO mice. To investigate the converse, we analyzed the behavior of TASK-1 and -3 KO mice after administering drugs with preferential efficacies at GABA A receptor subtypes: benzodiazepines ( diazepam and flurazepam, active at alpha 1 beta gamma 2, alpha 2 beta gamma 2, alpha 3 beta gamma 2, and alpha 5 beta gamma 2 subtypes), zolpidem (alpha 1 beta gamma 2 subtype), propofol (beta 2-3-containing receptors), gaboxadol (alpha 4 beta delta and alpha 6 beta delta subtypes), pregnanolone, and pentobarbital ( many subtypes). TASK-1 KO mice showed increased motor impairment in rotarod and beam-walking tests after diazepam and flurazepam administration but not after zolpidem. They also showed prolonged loss of righting reflex induced by propofol and pentobarbital. Autoradiography indicated no change in GABA(A) receptor ligand binding levels. These altered behavioral responses to GABAergic drugs suggest functional up-regulation of alpha 2 beta 2/3 gamma 2 and alpha 3 beta 2/3 gamma 2 receptor subtypes in TASK-1 KO mice. In addition, female, but not male, TASK-1 KO mice were more sensitive to gaboxadol, suggesting an increased influence of alpha 4 beta delta or alpha 6 beta delta subtypes. The benzodiazepine sensitivity of TASK-3 KO mice was marginally increased. Our results underline that TASK-1 channels perform such key functions in the brain that compensation is needed for their absence. Furthermore, because inhalation anesthetics act partially through GABA A receptors, the up- regulation of GABA A receptor function in TASK-1 KO mice might mask TASK-1 channel's significance as a target for inhalation anesthetics.