Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

• Published in: Nature (London) Vol. 554; no. 7692; pp. 317 - 322
• Main Authors: Yang, Yan, Cui, Yihui, Sang, Kangning, Dong, Yiyan, Ni, Zheyi, Ma, Shuangshuang, Hu, Hailan
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 15.02.2018
• Subjects: Action Potentials - drug effects; Affect - drug effects; Anhedonia - drug effects; Animal models; Animals; Antidepressants; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Bursting; Calcium; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; Calcium channels; Calcium channels (T-type); Calcium channels (voltage-gated); Calcium Channels - metabolism; Depression (Mood disorder); Depression - drug therapy; Disease Models, Animal; Firing pattern; Glutamic acid receptors; Habenula; Habenula - drug effects; Habenula - metabolism; Habenula - pathology; Habenula - radiation effects; Hedonic response; Ketamine; Ketamine - administration & dosage; Ketamine - pharmacology; Ketamine - therapeutic use; Luteinizing hormone; Male; Mental depression; Mental disorders; Mental health; Mice; Mood; N-Methyl-D-aspartic acid receptors; Neurons; Neurons - drug effects; Neurons - metabolism; Pharmacology; Physiological aspects; Pineal gland; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Reinforcement; Reward; Rodents; Synchronism; Synchronization; Theta Rhythm - drug effects
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature25509

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.