title: Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine.
abstract: Although the molecular mechanism is not clear, the clinically tested drug ketamine has rapid antidepressant action that does not require the multiple weeks of treatment needed for other antidepressant drugs to have an effect. We showed that ketamine potentiated Schaffer collateral-CA1 cell excitatory synaptic transmission in hippocampal slice preparations from rodents and enhanced the phosphorylation of the GluA1 subunit on Ser845of the AMPA-type glutamate receptor in the hippocampal area CA1. These effects persisted when γ-aminobutyric acid (GABA) receptors were pharmacologically blocked. Ketamine reduced behavioral despair in wild-type mice but had no effect in GluA1 S845A knock-in mutant mice. Presynaptic (CA3 pyramidal cell), but not postsynaptic (CA1 pyramidal cell), deletion of N-methyl-d-aspartate (NMDA)-type glutamate receptors eliminated the ketamine-induced enhancement of excitatory synaptic transmission in hippocampal slices and the antidepressant actions of ketamine in mice. The synaptic and behavioral actions of ketamine were completely occluded by inhibition or deletion of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1). Our results implicate presynaptic NMDA receptor inhibition followed by reduced activity of presynaptic HCN1 channels, which would result in an increase in glutamate release and postsynaptic glutamate receptor activity, as a mechanism of ketamine action. These data provide a mechanism for changes in synaptic activity that could explain the fast-acting antidepressant effects of this drug.
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.|The Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong 51030, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: The Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong 51030, China.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA.
authors.forename: Vitor Nagai
authors.initials: VN
authors.lastname: Yamaki
authors.affiliation: The Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang Road, Guangzhou, Guangdong 51030, China.
authors.forename: Mingfa
authors.initials: M
authors.lastname: Huang
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, 1135 Lincoln Drive, Carbondale, IL 62901, USA. cai001@siu.edu.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cai
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D056654:CA3 Region, Hippocampal / Q000378:metabolism*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology*; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007649:Ketamine; D015221:Potassium Channels; D018091:Receptors, AMPA; C578666:Hcn1 protein, mouse; C578667:Hcn1 protein, rat