How Ketamine Relieves Depression by Blocking Bursting In Habenula

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The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid and remarkable antidepressant actions. The mechanism by which ketamine relieves depression, often regarded as a medical breakthrough, has remained elusive to scientists and researchers.

Ketamine relieves depression by Blocking NMDAR-Dependent Bursting Activity


Here we show that Ketamine, a powerful anesthetic and dissociative drug, relieves depression by effectively blocking NMDAR-dependent bursting activity in the ‘anti-reward center’ known as the lateral habenula (LHb). This discovery has been demonstrated in both rat and mouse models of depression, highlighting the rapid and impactful antidepressant actions of ketamine.

LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine, the remarkable catalyst that unlocks the door to relief from the depths of depression.

Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia, yet the transformative touch of ketamine soothes the troubled mind, offering solace and respite, whispering a hopeful message that ‘Ketamine Relieves Depression’

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, supporting the profound impact of habenula blockade in how ketamine relieves depression.

Our results suggest a simple model whereby ketamine, a groundbreaking treatment known for its efficacy in relieving depression, quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons. This action effectively disinhibits downstream monoaminergic reward centres, offering a unique and promising approach for developing new rapid-acting antidepressants.


  1. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000)Article CAS Google Scholar
  2. Zarate, C. A. Jr et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006)Article CAS PubMed PubMed Central Google Scholar
  3. Maeng, S. et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63, 349–352 (2008)Article CAS PubMed PubMed Central Google Scholar
  4. Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010)Article ADS CAS PubMed PubMed Central Google Scholar
  5. Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011)Article CAS PubMed PubMed Central Google Scholar
  6. Zanos, P. et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486 (2016)Article ADS CAS PubMed PubMed Central Google Scholar
  7. Clements, J. A., Nimmo, W. S. & Grant, I. S. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J. Pharm. Sci. 71, 539–542 (1982)Article CAS PubMed Google Scholar
  8. Homayoun, H. & Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27, 11496–11500 (2007)Article CAS PubMed PubMed Central Google Scholar
  9. Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111–1115 (2007)Article ADS CAS PubMed Google Scholar
  10. Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212–217 (2012)ADS CAS PubMed PubMed Central Google Scholar
  11. Shabel, S. J., Proulx, C. D., Trias, A., Murphy, R. T. & Malinow, R. Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin. Neuron 74, 475–481 (2012)Article CAS PubMed PubMed Central Google Scholar
  12. Stamatakis, A. M. & Stuber, G. D. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat. Neurosci. 15, 1105–1107 (2012)Article CAS PubMed PubMed Central Google Scholar
  13. Stephenson-Jones, M. et al. A basal ganglia circuit for evaluating action outcomes. Nature 539, 289–293 (2016)Article ADS PubMed PubMed Central Google Scholar
  14. Morris, J. S., Smith, K. A., Cowen, P. J., Friston, K. J. & Dolan, R. J. Covariation of activity in habenula and dorsal raphé nuclei following tryptophan depletion. Neuroimage 10, 163–172 (1999)Article CAS PubMed Google Scholar
  15. Shumake, J., Edwards, E. & Gonzalez-Lima, F. Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. Brain Res. 963, 274–281 (2003)Article CAS PubMed Google Scholar
  16. Li, B. et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470, 535–539 (2011)Article ADS CAS PubMed PubMed Central Google Scholar
  17. Li, K. et al. βCaMKII in lateral habenula mediates core symptoms of depression. Science 341, 1016–1020 (2013)Article ADS CAS PubMed PubMed Central Google Scholar
  18. Lecca, S. et al. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat. Med. 22, 254–261 (2016)Article CAS PubMed PubMed Central Google Scholar
  19. Aizawa, H., Kobayashi, M., Tanaka, S., Fukai, T. & Okamoto, H. Molecular characterization of the subnuclei in rat habenula. J. Comp. Neurol. 520, 4051–4066 (2012)Article CAS PubMed Google Scholar
  20. Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013)Article ADS CAS Google Scholar
  21. Hu, H. Reward and aversion. Annu. Rev. Neurosci. 39, 297–324 (2016)Article CAS PubMed Google Scholar
  22. Jhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B. & Holland, P. C. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61, 786–800 (2009)Article CAS PubMed PubMed Central Google Scholar
  23. Tian, J. & Uchida, N. Habenula lesions reveal that multiple mechanisms underlie dopamine prediction errors. Neuron 87, 1304–1316 (2015)Article CAS PubMed PubMed Central Google Scholar
  24. Zhou, L. et al. Organization of functional long-range circuits controlling the activity of serotonergic neurons in the dorsal raphe nucleus. Cell Reports 18, 3018–3032 (2017)Article CAS PubMed Google Scholar
  25. Chang, S. Y. & Kim, U. Ionic mechanism of long-lasting discharges of action potentials triggered by membrane hyperpolarization in the medial lateral habenula. J. Neurosci. 24, 2172–2181 (2004)Article CAS PubMed PubMed Central Google Scholar
  26. Weiss, T. & Veh, R. W. Morphological and electrophysiological characteristics of neurons within identified subnuclei of the lateral habenula in rat brain slices. Neuroscience 172, 74–93 (2011)Article CAS PubMed Google Scholar
  27. McCormick, D. A. & Bal, T. Sleep and arousal: thalamocortical mechanisms. Annu. Rev. Neurosci. 20, 185–215 (1997)Article CAS PubMed Google Scholar
  28. Grillner, S., McClellan, A., Sigvardt, K., Wallén, P. & Wilén, M. Activation of NMDA-receptors elicits “fictive locomotion” in lamprey spinal cord in vitro. Acta Physiol. Scand. 113, 549–551 (1981)Article CAS PubMed Google Scholar
  29. Schiller, J., Major, G., Koester, H. J. & Schiller, Y. NMDA spikes in basal dendrites of cortical pyramidal neurons. Nature 404, 285–289 (2000)Article ADS CAS PubMed Google Scholar
  30. Zhu, Z. T., Munhall, A., Shen, K. Z. & Johnson, S. W. NMDA enhances a depolarization-activated inward current in subthalamic neurons. Neuropharmacology 49, 317–327 (2005)Article CAS PubMed Google Scholar
  31. Cheong, E. & Shin, H. S. T-type Ca2+ channels in normal and abnormal brain functions. Physiol. Rev. 93, 961–992 (2013)Article CAS PubMed Google Scholar
  32. Huguenard, J. R., Gutnick, M. J. & Prince, D. A. Transient Ca2+ currents in neurons isolated from rat lateral habenula. J. Neurophysiol. 70, 158–166 (1993)Article CAS PubMed Google Scholar
  33. Lisman, J. E. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20, 38–43 (1997)Article CAS PubMed Google Scholar
  34. Cui, Y. et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature (2018)Article ADS CAS PubMed Google Scholar
  35. Henn, F. A. & Vollmayr, B. Stress models of depression: forming genetically vulnerable strains. Neurosci. Biobehav. Rev. 29, 799–804 (2005)Article PubMed PubMed Central Google Scholar
  36. Gigliucci, V. et al. Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology (Berl.) 228, 157–166 (2013)Article CAS Google Scholar
  37. Gören, M. Z. & Onat, F. Ethosuximide: from bench to bedside. CNS Drug Rev. 13, 224–239 (2007)Article PubMed PubMed Central Google Scholar
  38. Gideons, E. S., Kavalali, E. T. & Monteggia, L. M. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc. Natl Acad. Sci. USA 111, 8649–8654 (2014)Article ADS CAS PubMed Google Scholar
  39. Ambert, N. et al. Computational studies of NMDA receptors: differential effects of neuronal activity on efficacy of competitive and non-competitive antagonists. Open Access Bioinformatics 2, 113–125 (2010)CAS PubMed PubMed Central Google Scholar
  40. Endo, M ., Kurachi, Y . & Mishina, M. Pharmacology of Ionic Channel Function: Activators and Inhibitors Vol. 147 (Springer Science & Business Media, 2012)
  41. Mehrke, G., Zong, X. G., Flockerzi, V. & Hofmann, F. The Ca++-channel blocker Ro 40-5967 blocks differently T-type and L-type Ca++ channels. J. Pharmacol. Exp. Ther. 271, 1483–1488 (1994)CAS