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 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.

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…Several reports have demonstrated that ketamine, and also (2R,6R)-HNK, applied in the perfusion solution enhance AMPARmediated synaptic transmission in the hippocampus. 6,20,38,[54][55][56][57][58] Other reports demonstrate a lack of effect of this treatment in the Ketamine alters mesolimbic synaptic plasticity N Yao et al same brain region 59 and suggest that the acute effect of ketamine is dependent on the concentration of this compound used and the location of the recording within the hippocampus (somatic vs dendritic recordings). 58 The ketamine-induced increase in hippocampal synaptic transmission is mimicked or blocked by NMDAR antagonists 55,57,58 and requires presynaptic NMDARs.…”

“…58 The ketamine-induced increase in hippocampal synaptic transmission is mimicked or blocked by NMDAR antagonists 55,57,58 and requires presynaptic NMDARs. 54 Furthermore, the increased glutamatergic transmission is not long-lasting, because the EPSP returns to baseline 2-3 h after ketamine perfusion. 54 Zhang et al 26,38,54 further demonstrated that ketamine applied in the perfusion solution or administered intraperitoneally increases the phosphorylation of Ser 845 -GluA1 and the expression of total GluA1 in the hippocampus.…”

“…54 Furthermore, the increased glutamatergic transmission is not long-lasting, because the EPSP returns to baseline 2-3 h after ketamine perfusion. 54 Zhang et al 26,38,54 further demonstrated that ketamine applied in the perfusion solution or administered intraperitoneally increases the phosphorylation of Ser 845 -GluA1 and the expression of total GluA1 in the hippocampus. Our observations in the NAc were made using an experimental paradigm different from the studies in the hippocampus.…”

“…88,89 Knock-in mice in which Ser 845 -GluA1 is replaced by alanine demonstrate loss of ketamineinduced synaptic potentiation in the hippocampus and impaired behavioral improvement induced by ketamine. 54 Future studies examining the effect of ketamine on behavior and LTP induction in the NAc of mice with a targeted alanine substitution of Ser 831 -GluA1 might reveal the role of this phosphorylation residue in mediating the antidepressant action of ketamine. Furthermore, the use of optogenetic tools, for example, will allow identifying the neurophysiological and behavioral consequences of an altered synaptic plasticity and function of AMPARs induced by ketamine in the NAc-VTA circuitry and in the different neuronal populations that compose these nuclei.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Application of ketamine to hippocampal slices induces AMPAR-mediated synaptic potentiation in the CA1 region [264], even in the absence of ongoing synaptic stimulation [43, 259]. Similar to ketamine, application of ( 2R,6R )-HNK increases AMPAR-mediated excitatory post-synaptic potentials recorded from the CA1 region of hippocampus [45] at a concentration that does not alter the NMDA-evoked responses in brain slices [45] or hippocampal cell cultures [107, 108].…”