Lateral Habenular Burst Firing as a Target of the Rapid Antidepressant Effects of Ketamine. Issue 3 (March 2019)

• Record Type: Journal Article
• Authors: Cui, Yihui; Hu, Shaohua; Hu, Hailan
• Is Part Of: Trends in neurosciences. Volume 42:Issue 3(2019)
• Page Start: 179
• Page End: 191
• Publication Date: 2019-03
• Subjects: habenular burst firing -- ketamine -- antidepressants -- depression; Neurology -- Periodicals; Neurophysiology -- Periodicals; Neurobiology -- Periodicals; 612.8
• DOI: 10.1016/j.tins.2018.12.002
• Languages: English
• ISSNs: 0166-2236

Abstract

Abstract : The revolutionary discovery of the rapid antidepressant ketamine has been a milestone in psychiatry field in the last half century. Unlike conventional antidepressants that often take weeks to months to show efficacy, ketamine causes rapid antidepressant effects, emerging as early as within 1 h after administration. However, how ketamine improves mood symptoms so quickly has remained elusive. Here, we first introduce the historical background of ketamine as a rapid antidepressant. We then discuss current hypotheses underlying ketamine's rapid antidepressant effects, with a focus on our latest discovery that ketamine silences NMDAR-dependent burst firing in the 'anti-reward center', the lateral habenula. While ketamine may act on many brain regions, we argue that its rapid antidepressant effects are critically dependent on ketamine's action in the lateral habenula, with this brain region acting as a primary site of action (or one among a few primary nodes). This molecular-, cellular-, and circuit-based mechanism advances our understanding of the etiology of depression and suggests a new conceptual framework for the rapid antidepressant effects of ketamine. Highlights: Ketamine, as a blocker of N-methyl D-aspartate (NMDA) receptors, has been shown to cause rapid antidepressant effects, sometimes as early as within 1 h after administration. While ketamine may act on many brain regions, recent findings from animal models indicate that its rapid antidepressant action is likely mediated by one or a limited number of regions. In particular, the lateral habenula (LHb) seems to act as a primary site of ketamine's rapid antidepressant action. As an 'anti-reward center', the LHb is known to mediate negative emotions and inhibit dopaminergic and serotonergic neurons in the brain's aminergic reward centers. During depression, LHb neurons display significant increase in burst firing and theta-band synchronization, which are reversed by ketamine. Since LHb bursts critically depend on NMDARs, ketamine can rapidly silence LHb bursts, thereby disinhibiting downstream reward centers to cause rapid improvement of depressive symptoms.