Forebrain HCN1 Channels Contribute to Hypnotic Actions of Ketamine

Abstract

Background Ketamine is a commonly used anesthetic but the mechanistic basis for its clinically relevant actions remains to be determined. We previously showed that HCN1 channels are inhibited by ketamine and demonstrated that global HCN1 knockout mice are two-fold less sensitive to hypnotic actions of ketamine. Although that work identified HCN1 channels as a viable molecular target for ketamine, it did not determine the relevant neural substrate. Methods To localize the brain region responsible for HCN1-mediated hypnotic actions of ketamine, we employed a conditional knockout strategy to delete HCN1 channels selectively in excitatory cells of the mouse forebrain. A combination of molecular, immunohistochemical and cellular electrophysiological approaches was used to verify conditional HCN1 deletion; a loss-of-righting reflex assay served to ascertain effects of forebrain HCN1 channel ablation on hypnotic actions of ketamine. Results In conditional knockout mice, HCN1 channels were selectively deleted in cortex and hippocampus, with expression retained in cerebellum. In cortical pyramidal neurons from forebrain-selective HCN1 knockout mice, effects of ketamine on HCN1-dependent membrane properties were absent; notably, ketamine was unable to evoke membrane hyperpolarization or enhance synaptic inputs. Finally, the half maximal effective concentration (EC50) for ketamine-induced loss-of-righting reflex was shifted to significantly higher concentrations (by ~31%). Conclusions These data indicate that forebrain principal cells represent a relevant neural substrate for HCN1-mediated hypnotic actions of ketamine. We suggest that ketamine inhibition of HCN1 shifts cortical neuron electroresponsive properties to contribute to ketamine-induced hypnosis.

The Role of Dendritic Signaling in the Anesthetic Suppression of Consciousness

“…49,63,64 Curiously, ketamine's effects on many brainstem and hypothalamic nuclei are quite opposite to those of the GABAergic and α2-adrenergic agents discussed before: it does not activate the sleep-promoting ventrolateral preoptic nucleus but, instead, promotes activity in the cholinergic, monoaminergic, and orexinergic arousal pathways. 138 Also, ketamine, as possibly the only general anesthetic, increases, rather than decreases, thalamic metabolism 145,146 (although the referenced studies used subanesthetic doses).…”

“…4D). 56 An inhibition of I h has been observed under the influence of several volatile and intravenous anesthetics, such as halothane, [57][58][59] enflurane, 57 isoflurane, 60 propofol, 61 pentobarbital, 62 and ketamine, 63,64 indicating that all of these agents can potentially disrupt the unique associative mechanism afforded by pyramidal cells between input to their somatic and dendritic compartments.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…An earlier study showed that ketamine inhibits muscarinic signaling in CHO cells as observed from intracellular Ca 2+ release in response to the agonist acetyl-b-methylcholine (Durieux, 1995). Finally, ketamine has been shown to inhibit the inward pacemaker current I h , which is mediated by ketamine binding to hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1) subunits in forebrain neurons Zhou et al, 2013). HCN1-KO mice are less sensitive to ketamine-induced hypnosis , indicating that this mechanism may explain the high-dose anesthetic effects, but no data are available on whether this mechanism is involved in other behavioral or neuroplasticity-inducing effects of ketamine.…”

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker ZD7288 Prevents Sevoflurane-Induced Hyperactivity in A Novel Mice Behavioral Model

“…Intravenous general anesthetics including ketamine, inhaled anesthetics like isoflurane and sevoflurane have been found to interact with HCN channels (17,18). Therefore, we hypothesized that HCN channel blocker could produce light sedative effect, which might attenuate sevoflurane-induced emergence agitation.…”

“…Previous studies demonstrate HCN channel deletion significantly affects potency of general anesthetic including ketamine, isoflurane and sevoflurane (17)(18)(19). For isoflurane and sevoflurane, HCN channel might be involved in their hypnotic and amnesic effects.…”