Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

  title={Ketamine blocks bursting in the lateral habenula to rapidly relieve depression},
  author={Yan Yang and Yihui Cui and Kangning Sang and Yiyan Dong and Zheyi Ni and Shuangshuang Ma and Hailan Hu},
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. [] Key Result 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.
NMDA receptor-dependent long-term depression in the lateral habenula: implications in physiology and depression
Findings show that NMDAR-dependent LTD in LHb plays an important role in regulating neuronal activity, which is probable to be excessively increased by repeated stress, via maintaining homeostasis in both synaptic and extrasynaptic regions of the LHb.
Decoding Depression: Insights from Glial and Ketamine Regulation of Neuronal Burst Firing in Lateral Habenula.
The latest discovery on how ketamine blocks N-methyl-D-aspartate receptor (NMDAR)-dependent burst firing of an "antireward" center in the brain, the lateral habenula (LHb), to mediate its antidepressant effects is described.
Mechanisms of ketamine action as an antidepressant
Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met
Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine
It is conceptualized that ketamine’s effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling, which reveals a novel neural plasticity-based mechanism for ketamine's acute and long-lasting antidepressant effects.
Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents
In a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.
Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model
It is suggested that ketamine represents a viable candidate for the treatment of poststroke depression but also thatketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.


NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses
It is shown that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor, suggesting the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast- acting antidepressants.
NMDAR inhibition-independent antidepressant actions of ketamine metabolites
It is shown that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice.
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
The results demonstrate that the effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamines.
Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism
Observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST, and molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5- HT transmission which underlies the antidepressant response.
Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses
This study recapitulate the ketamine and memantine clinical findings in mice, showing that ketamine, but not memantine, has antidepressant-like effects in behavioral models and provides a novel framework on the necessary functional requirements of NMDAR-mediated neurotransmission as a critical determinant necessary to elicit rapid antidepressant responses.
Synaptic potentiation onto habenula neurons in learned helplessness model of depression
Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats.
GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment
It is discovered that γ-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs to limit LHb activity in rodents, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior.
βCaMKII in Lateral Habenula Mediates Core Symptoms of Depression
expression of the β form of calcium/calmodulin-dependent protein kinase type II was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants.
Fluoxetine impairs GABAergic signaling in hippocampal slices from neonatal rats
Fluoxetine effects on GABAergic transmission were associated with a reduced firing rate of both principal cells and interneurons further suggesting that changes in network excitability account for GDPs disruption.