The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.
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We thank L.-S. Yu and J. Pan for performing LC–MS/MS; S.-M. Duan, X.-H. Zhang, X.-W. Chen, Y.-S. Shu, X. Ju, C. Lohmann and W. Yang for advice on experimental design and comments on the manuscript; and N. Lin, L. Zhang and K.-F. Liu for consultation on in vivo recording. This work was supported by grants from the National Key R&D Program of China (2016YFA0501000), the National Natural Science Foundation of China (91432108, 31225010, and 81527901) to H.H. and (81600954) to Y.Y., and the 111 project (B13026) to H. H.
H.H., Y.Y. and Y.C. are inventors on two patent applications (201710322647.X and 201710322646.5) filed on the basis on this work. The remaining authors declare that they have no competing interests.
Reviewer Information Nature thanks P. Kenny, H.-S. Shin and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Figure 1 Representative ion chromatograms of separation of ketamine by LC–MS/MS and OFT results for different drug treatments.
a, Antidepressant response to systemic ketamine injection (25 mg kg–1, i.p.) in FST 1 h after treatment in cLH rats. n = 10, 8, 6 for wild-type rats injected with saline, cLH rats injected with saline, and cLH rats injected with ketamine, respectively. b, c, OFT of cLH rats after bilateral infusion of ketamine (25 μg, 1 μl each side) or mibefradil (10 nmol, 1 μl each side; b), AP5 (40 nmol, 1 μl each side) or NBQX (1 nmol, 1 μl each side; c) into the LHb. n = 7, 10, 6 rats (b) and 8, 9, 9 rats (c) for saline, ketamine and mibefradil, respectively. d, OFT of CRS mice 1 h after intraperitoneal injection of saline or ethosuximide. n = 6, 9 mice for saline and ethosuximide, respectively. e–g, Representative ion chromatograms of separation of ketamine including double blank (e), brain calibrator spiked with 100 ng ml–1 ketamine (KET) (f) and a habenular sample from a cLH rat bilaterally infused with 25 μg μl–1 ketamine into the LHb 1 h earlier (g). Fluvoxamine (FFSM) is used as the internal standard. Data are mean ± s.e.m.; *** P < 0.001, **** P < 0.0001; n.s., not significant. One-way ANOVA (a–c), two-tailed Mann–Whitney test and unpaired t-test (d).
Extended Data Figure 2 I–V relationship, input resistance and burst duration are not changed in animal models of depression.
a–d, I–V plots (a), input resistance (b), intra-burst frequency (c) and inter-burst frequency (d) for LHb neurons in brain slices from mice and rats. Note that intra-burst frequency (c) but not inter-burst frequency (d) reversely correlates with RMPs. n = 20 neurons per group, 5 wild-type and 3 cLH rats (b); n = 53 neurons, 8 mice and 12 rats (c, d). e–i, Burst duration in animal models of depression recorded in brain slices in vitro (e–g) and in behaving animals in vivo (h, i). e, Representative trace of a typical burst in an in vitro recording. It consists of a depolarizing wave and a high-frequency train of action potentials. The duration of the line indicated by the black arrow at half-maximum amplitude of the area under the red dash line is defined as the half width of burst duration; the duration between the first and last shoots (intra burst spikes) within one burst is defined as the shoot duration. f, g, Half widths of burst duration (f) and shoot duration (g) do not differ between cLH and wild-type rats. n = 10, 20 neurons, 7 wild-type and 5 cLH rats. h, Representative trace of an LHb neuron (pink shades indicate burst events) recorded in vivo. An enlarged view of a typical burst on the right shows the definition of burst duration, which is the time interval between the first and last spike within the same burst. i, Burst duration of LHb neurons from in vivo recording do not differ between control and CRS mice. n = 35, 33 neurons, 5 control and 5 CRS mice. Data are mean ± s.e.m.; n.s., not significant. Two-tailed unpaired t-test (b, f, g) and Mann–Whitney test (i).
Extended Data Figure 3 Chronic restraint stress induces reliable depression-like phenotypes and increased burst firing, which can be reversed by ketamine.
a, b, CRS induces increased immobility and decreased latency to immobility in the FST (a) and decreases sucrose preference in the SPT (b). n = 8, 14 mice (a) and 7, 8 mice (b) for control and CRS group, respectively. c, CRS increases locomotion in the OFT. n = 8 mice per group. d, e, Ketamine suppresses immobility of CRS mice in the FST (d) and increases sucrose preference (e) in CRS mice. f, Ketamine decreases locomotion of CRS mice in the OFT. n = 8, 12 mice (d, f) and 14, 21 mice (e) for saline and ketamine groups, respectively. g–j, Burst firing is significantly increased in CRS mice, and this increase is reversed by ketamine (i.p., 10 mg kg–1). g, Whole-cell patch-clamp recording sites across different subregions of LHb in mice. h, Pie charts illustrating the per cent abundance of the three types of LHb neurons. i, Bar graph illustrating the percentage of burst- and tonic-type spikes in all spikes recorded. j, Histogram of distribution of inter-spike intervals (ISIs). n = 63, 69, 57 neurons, 4 control, saline-treated mice, 3 CRS, saline-treated mice and 5 CRS, ketamine-treated mice. Data are mean ± s.e.m.; *P < 0.05, **P < 0.01, ****P < 0.0001, n.s., not significant. Two-tailed Mann–Whitney test and unpaired t-test (a– f), Chi-square test (h), Fisher’s exact test (i).
a, Histology of recording site. Arrowhead indicates the electrical lesion by tetrodes. b, Representative waveform clusters of two isolated LHb units in the respective four channels of a tetrode (left) and principal-component analysis (PCA) clustering display of these two units (right). c, ISIs between consecutive spikes in relation to their positions within the burst (120 bursts from in vitro recording). d, Example recording trace (upper) and spike train (bottom) of an irregular-firing LHb neuron from an in vivo recording. Bursts (blue sticks) are identified by ISI method (see Methods for details): 1, ISI to start burst; 2, ISI to end burst; 3, inter-burst interval. e, Histogram of ISI distribution (bin, 2.5 ms) from in vivo recording. f–i, Mean of total and tonic firing rates (f, h), intra- and inter-burst frequencies, and number of spikes per burst (g, i) of neurons recorded in vivo from control mice, CRS mice and CRS mice 1 h before and after ketamine injection (i.p., 10 mg kg–1). n = 35, 33 neurons (f, g) and 18, 18 neurons (h, i), 5 control and 5 CRS mice. j, STAs of neurons recorded in vivo from control mice, CRS mice, and CRS mice after ketamine injection (i.p., 10 mg kg–1). Note that the distance between the neighbouring troughs is around 140 ms (corresponding to 7 Hz) in CRS mice. Data are mean ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, n.s., not significant. Two-tailed Mann–Whitney test and unpaired t-test (f, g), two-tailed Wilcoxon matched-pairs signed rank test and paired t-test (h, i).
a, Example traces showing evoked EPSCs when cells were held at –80 mV. NMDAR EPSCs were isolated by application of picrotoxin (100 μM) and NBQX (10 μM) in Mg2+-free ACSF, and confirmed by AP5 (100 μM) blockade. b, Amplitudes of NMDAR EPSCs under different voltages (EPSCs are recorded under 0 Mg2+, picrotoxin and NBQX). Note that isolated NMDAR EPSCs are completely blocked by AP5. c–f, Ketamine (c), AP5 (d), NBQX (e) and mibefradil (f) do not affect RMPs of LHb neurons. n = 10 neurons, 5 rats (c); n = 17 neurons, 6 rats (d); n = 11 neurons, 6 rats (e); n = 10 neurons, 3 rats (f). g, ZD7288 causes a small but significant hyperpolarization of LHb neurons. n = 9 neurons, 4 rats. h, Example mEPSC traces before (black) and after (red) perfusion of ketamine (100 μM, see Methods) measured in a whole-cell configuration (cells were held at –60 mV) from LHb neurons. i, j, Cumulative distribution of mEPSC amplitude (i) or mEPSC inter-events interval and average frequency (j) of neurons before (black) or after (red) ketamine treatment. Each line represents values before or after treatment with ketamine from the same LHb neuron. n = 9 neurons, 2 rats. Data are mean ± s.e.m.; *P < 0.05, n.s., not significant. Two-tailed paired t-test.
Extended Data Figure 6 Voltage dependency of LHb bursts and pharmacological manipulation of hyperpolarization-triggered rebound bursts in LHb.
a, Representative trace of an LHb neuron transformed from bursting to tonic-firing mode with a ramp-like current injection, showing bursting at more hyperpolarized potentials and tonic firing at more depolarized potentials. Spikes in bursting and tonic-firing mode are shown in blue and black, respectively. b–d, Correlations of membrane potential with intra-burst frequency (b), burst duration (c) and intra-burst spike number (d) generated by current ramps. n = 104 neurons, 14 rats. e, f, Example traces of a spontaneously tonic-firing neuron transformed to burst-firing mode by hyperpolarization (e), and a spontaneously bursting neuron transformed to tonic-firing mode by depolarization (f). g–k, Example traces (left) and statistics (right) showing effects of ketamine (g), AP5 (h), mibefradil (i), ZD7288 (j) and fluoxetine (k) on rebound bursts induced by a transient hyperpolarizing current step. Current injection steps are illustrated under the bottom of the trace. n = 9 neurons, 2 rats (g); n = 12 neurons, 5 rats (h); n = 14 neurons, 2 rats (i); n = 8 neurons, 3 rats (j); n = 6 neurons, 2 rats (k). Data are mean ± s.e.m.; *P < 0.05, ****P < 0.0001, n.s., not significant. Two-tailed paired t-test.
a, Voltage steps used to isolate T-VSCC currents, starting from a holding potential of −50 mV before being increased to conditioning potential (−100 mV) for 1 s preceding the command steps (5 mV, 0.1 Hz per step increment). b, LHb T-VSCC currents (right column) are obtained by subtraction of recorded traces without (left) mibefradil from those with mibefradil (10 μM, middle). The maximum of isolated T-VSCC current is obtained at −50 mV. c, d, No difference in LHb T-VSCC currents is detected between wild-type and cLH rats (c) or control and CRS mice (d). n = 4 neurons per group from 2 wild-type and 2 cLH rats (c); n = 5 neurons per group from 2 control and 2 C57 mice (d). e, f, Scatter plots showing that neuronal RMPs are more hyperpolarized in cLH rats (e) and CRS mice (f) than in controls. n = 45 neurons per group from 5 wild-type and 4 cLH rats (e); n = 50 neurons per group from 4 control and 3 C57 mice (f). Data are mean ± s.e.m.; ***P < 0.001, ****P < 0.0001. Two-tailed unpaired t-test (e, f).
a, Scheme of a single compartment model of an LHb neuron (see Methods). b, The contribution of NMDAR current INMDAR and T-VSCC current IT during bursts derived from simulation. c, RMP-dependent firing mode of the LHb model neuron. Spikes in bursting mode are shown in blue. Spikes in tonic and silent firing mode are shown in black. d, The correlation between RMPs and intra-burst frequencies of the LHb model neuron. e, f, Example trace (left) and statistics (right) showing in silico effects of ketamine (set NMDAR conductance gNMDAR = 0, e) or mibefradil (gT-VSCC = 0, f) on spontaneous bursts in the LHb model neuron. The bursting probability was evaluated across ten independent trials with simulated synaptic inputs. Note that in silico knockout of NMDAR or T-VSCC current from the model abolished the bursts, which matched experimental observations (Fig. 3a, d, 4a). g, h, Example trace (left) and statistics (right) showing in silico effects of NBQX (gAMPAR = 0, g) or AMPA (gAMPAR increased from 8 to 15 μS cm−2, h) on spontaneous bursts in the LHb model neuron. n = 10 simulations (e–h). i, An example trace summarizing the ionic components and channel mechanisms involved in LHb bursting: hyperpolarization of neurons to membrane potentials negative to −55 mV slowly de-inactivates T-VSCC. IT continues to grow as the de-inactivated T-VSCCs increase, leading to a transient Ca2+ plateau potential. The Ca2+ plateau helps remove the magnesium blockade of NMDARs while T-VSCC inactivates rapidly during the depolarization. After the Ca2+ plateau reaches approximately −45 mV, INMDA dominates the driving force to further depolarize RMP to the threshold for Na spike generation. As RMP falls back to below −55 mV it de-inactivates IT and results in the intrinsic propensity of LHb neurons to generate the next cycle of bursting. Data are mean ± s.e.m.; ****P < 0.0001. Two-tailed paired t-test.
a, b, Example traces (left) and statistics (right, sampled within 3 min before and 1 min after drug application) showing effects of AMPA (a) or picrotoxin (b) on spontaneous bursts in the LHb. n = 8 neurons, 2 rats (a); n = 6 neurons, 3 rats (b). Data are mean ± s.e.m.; *P < 0.05, ***P < 0.001. Two-tailed paired t-test.
Extended Data Figure 10 Additional behavioural results of eNpHR3.0- or oChIEF-based photostimulation.
a, Representative trace showing that LHb neurons can follow only the first of the five 100-Hz pulsed blue light stimulations in a pulsed 100-Hz protocol in LHb brain slices infected with AAV2/9-oChIEF. Percentage of responsive neurons shown on the right. b–d, Pulsed 100-Hz photostimulation of mice expressing oChIEF does not change locomotion in the OFT (b), and does not induce depressive phenotypes in the FST (c) or SPT (d). n = 6, 7 mice (b, c) and 5, 5 mice (d) for oChIEF and eGFP groups, respectively. e, Representative trace showing LHb neurons following a 5-Hz tonic blue light stimulation protocol in LHb brain slices infected with AAV2/9- oChIEF. Percentage of responsive neurons shown on the right. f–h, 5-Hz photostimulation of LHb in mice expressing oChIEF does not change locomotion in the OFT (f) and does not induce depressive phenotypes in the FST (g) or SPT (h). n = 7, 6 mice (f); 6, 6 mice (g) and 5, 12 mice (h) for oChIEF and eGFP groups, respectively. i, 20-Hz tonic photostimulation of the LHb in mice expressing oChIEF does not cause RTPA. Note that this result is different from 20-Hz optogenetic stimulation of a presynaptic input from the entopeduncular nucleus into the LHb, which caused aversion11. n = 5, 7 mice for oChIEF and eGFP group. j, k, eNpHR3.0-driven burst does not change speed of movement in RTPA (j) or affect locomotion in the OFT (k). n = 11, 7 mice (j) and 13, 21 mice (k) for NpHR and eGFP group, respectively. Data are mean ± s.e.m.; n.s., not significant. Two-way ANOVA (b, d, f, h, k), two-tailed unpaired t-test (c, g, i) and paired t-test (j).
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Yang, Y., Cui, Y., Sang, K. et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554, 317–322 (2018). https://doi.org/10.1038/nature25509
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