title: 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. The authors previously showed that HCN1 channels are inhibited by ketamine and demonstrated that global HCN1 knockout mice are twofold 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, the authors used a conditional knockout strategy to delete HCN1 channels selectively in excitatory cells of the mouse forebrain. A combination of molecular, immunohistochemical, and cellular electrophysiologic 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 EC50 for ketamine-induced loss-of-righting reflex was shifted to significantly higher concentrations (by approximately 31%).
  
  
  CONCLUSIONS
  These data indicate that forebrain principal cells represent a relevant neural substrate for HCN1-mediated hypnotic actions of ketamine. The authors suggest that ketamine inhibition of HCN1 shifts cortical neuron electroresponsive properties to contribute to ketamine-induced hypnosis.
authors: Department of Anesthesiology, Laboratory of Anesthesia & CCM, Translational Neuroscience Center, State Key Laboratory of Biotherapy of Cancer, West China Hospital of Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors: Cheng
authors: C
authors: Zhou
authors: Jennifer E
authors: JE
authors: Douglas
authors: Natasha N
authors: NN
authors: Kumar
authors: Shaofang
authors: S
authors: Shu
authors: Douglas A
authors: DA
authors: Bayliss
authors: Xiangdong
authors: X
authors: Chen
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D015221:Potassium Channels; D016548:Prosencephalon / Q000187:drug effects*
chemical_list: D000700:Analgesics; D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D006993:Hypnotics and Sedatives; D015221:Potassium Channels; D007649:Ketamine
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