Ketamine induces opposite changes in AMPA receptor calcium permeability in the ventral tegmental area and nucleus accumbens

Abstract

Ketamine elicits rapid and durable antidepressant actions in treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression. The mechanisms might involve the induction of metaplasticity in brain regions associated with reward-related behaviors, mood, and hedonic drive, particularly the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We have examined if ketamine alters the insertion of the GluA2 subunit of AMPA receptors (AMPAR), which determines calcium permeability of the channel, at glutamatergic synapses onto dopamine (DA) neurons in the VTA and spiny projection neurons (SPNs) in the Core region of the NAc. Mice received one injection of either saline or a low dose of ketamine 24 h before electrophysiological recordings were performed. We found that GluA2-lacking calcium-permeable (CP) AMPARs were present in DA neurons in the VTA of mice treated with saline, and that ketamine-induced the removal of a fraction of these receptors. In NAc SPNs, ketamine induced the opposite change, i.e., GluA2-lacking CP-AMPARs were inserted at glutamatergic synapses. Ketamine-induced metaplasticity was independent of group I metabotropic glutamate receptors (mGluRs) because an agonist of these receptors had similar effects on glutamatergic transmission in mice treated with saline and in mice treated with ketamine in both VTA DA neurons and in the NAc. Thus, ketamine reduces the insertion of CP-AMPARs in VTA DA neurons and induces their insertion in the NAc. The mechanism by which ketamine elicits antidepressant actions might thus involve an alteration in the contribution of GluA2 to AMPARs thereby modulating synaptic plasticity in the mesolimbic circuit.

Fig. 1. Ketamine promotes the insertion of calcium impermeable AMPARs at glutamatergic synapses onto VTA DA neurons.

a Schema illustrating the experimental design. b I/V relationships of AMPAR-EPSCs amplitude normalized by −80mV in VTA DA neurons from saline- and ketamine-treated mice. §P = 0.0262, two-way ANOVA. c Rectification index from the neurons in (a) Saline: 0.31 ± 0.025 (n = 14 neurons from 4 mice), ketamine: 0.41 ± 0.016 (n = 11 neurons from 5 mice). **P = 0.0032 unpaired t-test. d Example traces of AMPAR-EPSCs recorded at holding potentials between −80 mV and +40 mV with 20 mV increments in a VTA DA neuron from a saline-treated mouse and in a VTA DA neuron from a ketamine-treated mouse. Scale bars represent 200 pA and 10 ms for both neurons. e Effect of bath application of NASPM (25 μM), a GluA2-lacking CP-AMPAR blocker; % of baseline in saline-treated mice: 70.67 ± 4.2 (n = 7 neurons from 4 mice), and in ketamine-treated mice: 88.56 ± 4.2 (n = 7 neurons from 4 mice). *P = 0.0107 unpaired t-test. ^#P = 0.0317, ^##P = 0.001 paired t-test. f Example traces of AMPAR-EPSCs before (baseline) and during the application of NASPM in the perfusion solution in a VTA DA neuron from a saline-treated mouse and in a VTA DA neuron from a ketamine-treated mouse. Scale bars represent 100 pA and 10 ms for both neurons. g AMPAR-EPSC tau (ms) in saline-treated mice: 1.43 ± 0.06 (n = 20 neurons from 7 mice), and in ketamine-treated mice: 1.8 ± 0.08 (n = 28 neurons from 10 mice). **P = 0.0014 unpaired t-test. h Superimposed AMPAR-EPSCs traces illustrating the slower kinetics in a VTA DA neuron from a ketamine-treated mouse compared to that recorded in a VTA DA neuron from a saline-treated mouse. Scale bar represents 10 ms for both neurons. i Schema summarizing the effect of ketamine on the involvement of GluA2 in synaptic AMPARs in VTA DA neurons.

Fig. 2. Ketamine promotes the insertion of CP-AMPARs at glutamatergic synapses on NAc SPNs.

a Schema illustrating the experimental design. b I/V relationships of AMPAR-EPSCs amplitude normalized by −80mV in NAc SPNs from saline- and ketamine-treated mice. c Rectification index from the neurons in (a) Saline: 0.481 ± 0.04 (n = 9 neurons from 5 mice), Ketamine: 0.335 ± 0.04 (n = 7 neurons from 3 mice). *P = 0.0197 unpaired t-test. d Example traces of AMPAR-EPSCs recorded at holding potentials between −80 mV and +40 mV with 20 mV increments in a NAc SPN from a saline-treated mouse and in a NAc SPN from a ketamine-treated mouse. Scale bars represent 100 pA and 20 ms for both neurons. e Effect of bath application of NASPM (25 μM); % of baseline in saline-treated mice: 101.9 ± 5.2 (n = 8 neurons from 4 mice), and in ketamine-treated mice: 81.6 ± 5.7 (n = 6 neurons from 4 mice), *P = 0.0228 unpaired t-test. ^#P = 0.0237 paired t-test. f Example traces of AMPAR-EPSCs before (baseline) and during the application of NASPM in the perfusion solution in a NAc SPN from a saline-treated mouse and in a NAc SPN from a ketamine-treated mouse. Scale bars represent 100 pA and 20 ms for both neurons. g AMPAR-EPSC tau (ms) in saline-treated mice: 7.3 ± 0.4 (n = 19 neurons from 5 mice), and in ketamine-treated mice: 6.57 ± 0.5 (n = 14 neurons from 4 mice), P = 0.2499 unpaired t-test. h Superimposed AMPAR-EPSCs traces illustrating similar kinetics in a NAc SPN from a ketamine-treated mouse and in a NAc SPN from a saline-treated mouse. Scale bar represents 20 ms for both neurons. i Schema summarizing the effect of ketamine on the involvement of GluA2 in synaptic AMPARs in NAc SPNs.

Fig. 3. Effect of DHPG on glutamatergic synaptic transmission is not altered by ketamine.

a, d Time course of the effect of bath application of DHPG (a: 20 μM; b: 100 μM), a group I mGluR agonist, on the amplitude of AMPAR-EPSCs in VTA DA neurons (a) and fEPSP/PS in the NAc (d) in saline- and ketamine-treated mice. b, e Percent of baseline in VTA DA neurons (b): saline 80.3 ± 6.8 (n = 6 neurons from 4 mice), ketamine 81.2 ± 5.9 (n = 6 neurons from 3 mice). ^#P = 0.0332 and 0.0252 paired t-test. P = 0.9169 unpaired t-test. Percent of baseline in the NAc (e): saline 108.0 ± 8.6 (n = 7 slices from 4 mice), ketamine 107.9 ± 6.2 (n = 4 slices from 3 mice), P = 0.9917 unpaired t-test. c, f Example traces of AMPAR-EPSCs before (baseline) and during the application of DHPG in the perfusion solution in VTA DA neurons (c). Scale bars: 100 pA/20 ms for the neuron from a saline-treated mouse and 50 pA/20 ms for the neuron from a ketamine-treated mouse. Example traces of fEPSP/PSs in the NAc before (baseline) and during the application of DHPG (f). Scale bars: 1 mV/10 ms for both slices.