Received for publication June 11, 2008.
Revised July 24, 2008.
Accepted for publication July 24, 2008.

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

Abstract

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 these channels’ anticipated functions and importance. TASK-1/-3 channel expression can compensate for the absence of GABA_A receptors in the 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 12, 22, 32 and 52 subtypes), zolpidem (12 subtype), propofol (2-3-containing receptors), gaboxadol (4 and 6 subtypes), pregnanolone and pentobarbital (many subtypes). TASK-1 KO mice showed increased motor impairment in rotarod and beam walking tests after diazepam and flurazepam, 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 changed behavioral responses to GABAergic drugs suggest functional upregulation of 22/32 and 32/32 receptor subtypes in TASK-1 KO mice. Additionally, female, but not male TASK-1 KO mice were more sensitive to gaboxadol, suggesting an increased influence of 4 and 6 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. Further, because inhalational anesthetics activate GABA_A receptors, the upregulation of GABA_A receptor function in TASK-1 KO mice might produce an underestimate of TASK-1 channel's significance as a target for inhalational anesthetics.

Key words: GABA-A receptor, anesthetic, benzodiazepine, knockout mice, motor, potassium channel