Science (New York, N.Y.)
August 9, 2024
Min Chen, Shuangshuang Ma, Hanxiao Liu et al.
87 citations
Ketamine, a rapid antidepressant, works by blocking N-methyl-d-aspartate receptors (NMDARs) specifically in the lateral habenula (LHb) of the brain, not in the hippocampus. In depressive-like mice, this regional selectivity depends on local neural activity and the availability of extrasynaptic NMDARs. Activating the hippocampus or inactivating the LHb reversed this sensitivity. Removing NMDARs from the LHb prevented ketamine's antidepressant effects and blocked the drug-induced rise in serotonin and brain-derived neurotrophic factor in the hippocampus. Identifying this primary brain target should help design more precise antidepressant treatments.
Neuron
February 5, 2025
Marc Duque, Alex B Chen, Eric Hsu et al.
27 citations
A brief exposure to ketamine can produce lasting changes in behavior and mood. In larval zebrafish, a short ketamine treatment suppressed the passive "giving-up" response that normally occurs when swimming fails to produce forward movement. Whole-brain imaging showed that ketamine initially hyperactivates a circuit involving norepinephrine and astrocytes, which controls this passivity. After ketamine is removed, the same circuit becomes less sensitive to futility, resulting in long-term increased perseverance. Experiments using pharmacology, chemogenetics, and optogenetics confirmed that norepinephrine and astrocytes are both necessary and sufficient for this effect. In adult mice, astrocytes in the cortex were similarly activated during a futility test, and ketamine also caused astrocyte hyperactivation. The cross-species conservation of this mechanism suggests new strategies for treating affective disorders.
Nature
November 5, 2025
Chenyu Yue, Nan Wang, Haojiang Zhai et al.
22 citations
Adenosine signaling is identified as the central mechanism underlying the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT). Experiments in mice using genetically encoded adenosine sensors and real-time optical recordings show that both therapies cause strong adenosine surges in mood-regulatory brain regions such as the medial prefrontal cortex and hippocampus. Disrupting A1 and A2A adenosine receptors genetically or pharmacologically abolishes the therapeutic effects, establishing adenosine's essential role. Ketamine increases adenosine by modulating cellular metabolism without causing neuronal hyperactivity. Newly developed ketamine derivatives that enhance adenosine signaling show improved antidepressant efficacy with fewer side effects. Acute intermittent hypoxia, a non-pharmacological intervention, also increases brain adenosine and produces antidepressant effects, paralleling ketamine and ECT.