Abstract

TASK channels are acid-sensitive and anesthetic-activated members of the family of two-pore-domain potassium channels. We have made the surprising discovery that the genetic ablation of TASK-3 channels eliminates a specific type of theta oscillation in the cortical electroencephalogram (EEG) resembling type II theta (4-9 Hz), which is thought to be important in processing sensory stimuli before initiating motor activity. In contrast, ablation of TASK-1 channels has no effect on theta oscillations. Despite the absence of type II theta oscillations in the TASK-3 knockout (KO) mice, the related type I theta, which has certain neuronal pathways in common and is involved in exploratory behavior, is unaffected. In addition to the absence of type II theta oscillations, the TASK-3 KO animals show marked alterations in both anesthetic sensitivity and natural sleep behavior. Their sensitivity to halothane, a potent activator of TASK channels, is greatly reduced, whereas their sensitivity to cyclopropane, which does not activate TASK-3 channels, is unchanged. The TASK-3 KO animals exhibit a slower progression from their waking to sleeping states and, during their sleeping period, their sleep episodes as well as their REM theta oscillations are more fragmented. These results imply a previously unexpected role for TASK-3 channels in the cellular mechanisms underlying these behaviors and suggest that endogenous modulators of these channels may regulate theta oscillations.