Research ArticleNeuroscience

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

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Science Signaling  13 Dec 2016:
Vol. 9, Issue 458, pp. ra123
DOI: 10.1126/scisignal.aai7884

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Keys to the rapid antidepressant action of ketamine

Ketamine is a clinically used “dissociative analgesic” for pain management and a rapidly acting antidepressant for patients that have not responded to other treatments. Ketamine enhances the activity of AMPA-type glutamate receptors. Zhang et al. showed that this is an indirect effect, involving inhibition of presynaptic NMDA receptors and reduced activity of HCN1 (hyperpolarization-activated cyclic nucleotide–gated channel 1). Ketamine stimulated the phosphorylation of the GluA1 subunit of the postsynaptic AMPA receptors, and mice with a form of this subunit that lacked the phosphorylation site exhibited neither the electrophysiological effects of ketamine nor the antidepressant effects of ketamine. Ketamine was ineffective in changing behavioral responses in mice lacking presynaptic CA3 NMDA receptors or HCN1 channels, and the electrophysiological analysis indicated that ketamine inhibited presynaptic NMDA receptors to reduce HCN1 function, which would promote glutamate release and increase AMPA receptor phosphorylation and activity. This study puts the mechanism of ketamine action on the presynaptic side of the synapse.


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 Ser845 of 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.

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