Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-Acting antidepressant responses of ketamine

Ke Zhang, Ting Xu, Zhongmin Yuan, Zhisheng Wei, Vitor Nagai Yamaki, Mingfa Huang, Richard L. Huganir, Xiang Cai

Research output: Contribution to journalArticlepeer-review

Abstract

Although the molecular mechanism is not clear, the clinically tested drug ketamine has rapid antidepressant actio that does not require the multiple weeks of treatment needed for other antidepressant drugs to have an effect. W showed that ketamine potentiated Schaffer collateral-CA1 cell excitatory synaptic transmission in hippocampal slic preparations from rodents and enhanced the phosphorylation of the GluA1 subunit on Ser845 of the AMPA-Typ glutamate receptor in the hippocampal area CA1. These effects persisted when g-Aminobutyric acid (GABA) receptor were pharmacologically blocked. Ketamine reduced behavioral despair in wild-Type mice but had no effec in GluA1 S845A knock-in mutant mice. Presynaptic (CA3 pyramidal cell), but not postsynaptic (CA1 pyramida cell), deletion of N-methyl-D-Aspartate (NMDA)-type glutamate receptors eliminated the ketamine-induced enhancemen of excitatory synaptic transmission in hippocampal slices and the antidepressant actions of ketamin in mice. The synaptic and behavioral actions of ketamine were completely occluded by inhibition or deletion o the hyperpolarization-Activated cyclic nucleotide-gated channel 1 (HCN1). Our results implicate presynaptic NMD receptor inhibition followed by reduced activity of presynaptic HCN1 channels, which would result in an increas 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 antidepressan effects of this drug.

Original languageEnglish (US)
Article numberra123
JournalScience signaling
Volume9
Issue number458
DOIs
StatePublished - Dec 13 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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