HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine

Ketamine has important anesthetic, analgesic, and psychotropic actions. It is widely believed that NMDA receptor inhibition accounts for ketamine actions, but there remains a dearth of behavioral evidence to support this hypothesis. Here, we present an alternative, behaviorally relevant molecular substrate for anesthetic effects of ketamine: the HCN1 pacemaker channels that underlie a neuronal hyperpolarization-activated cationic current (I(h)). Ketamine caused subunit-specific inhibition of recombinant HCN1-containing channels and neuronal I(h) at clinically relevant concentrations; the channels were more potently inhibited by S-(+)-ketamine than racemic ketamine, consistent with anesthetic actions of the compounds. In cortical pyramidal neurons from wild-type, but not HCN1 knock-out mice, ketamine induced membrane hyperpolarization and enhanced dendritosomatic synaptic coupling; both effects are known to promote cortical synchronization and support slow cortical rhythms, like those accompanying anesthetic-induced hypnosis. Accordingly, we found that the potency for ketamine to provoke a loss-of-righting reflex, a behavioral correlate of hypnosis, was strongly reduced in HCN1 knock-out mice. In addition, hypnotic sensitivity to two other intravenous anesthetics in HCN1 knock-out mice matched effects on HCN1 channels; propofol selectively inhibited HCN1 channels and propofol sensitivity was diminished in HCN1 knock-out mice, whereas etomidate had no effect on HCN1 channels and hypnotic sensitivity to etomidate was unaffected by HCN1 gene deletion. These data advance HCN1 channels as a novel molecular target for ketamine, provide a plausible neuronal mechanism for enhanced cortical synchronization during anesthetic-induced hypnosis and suggest that HCN1 channels might contribute to other unexplained actions of ketamine.