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BEHAVIORAL PHARMACOLOGY

K⁺ Channel TASK-1 Knockout Mice Show Enhanced Sensitivities to Ataxic and Hypnotic Effects of GABA_A Receptor Ligands

Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland (A.-M.L., E.L., E.R.K.); Instituto de Neurociencas de Alicante, Consejo Superior de Investigaciones Cientificas-Universidad Miguel Hernández, Sant Joan d'Alacant, Spain (M.I.A.); Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom (W.W.); and Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland (P.H.R.)

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 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 1β2, 2β2, 3β2, and 5β2 subtypes), zolpidem (1β2 subtype), propofol (β2–3-containing receptors), gaboxadol (4β and 6β 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 2β2/32 and 3β2/32 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 4β or 6β 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.

Address correspondence to: Dr. Anni-Maija Linden, Institute of Biomedicine, Pharmacology, University of Helsinki, POB 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. E-mail: anni-maija.linden{at}helsinki.fi