Ketamine exerts its sustained antidepressant effects via cell-type-specific 
regulation of Kcnq2

Lopez, Juan Pablo; Luecken, Malte D.; Brivio, Elena; Karamihalev, Stoyo; Kos, Aron; De Donno, Carlo; Benjamin, Asaf; Yang, Huanqing; Dick, Alec L. W.; Stoffel, Rainer; Flachskamm, Cornelia; Ressle, Andrea; Roeh, Simone; Huettl, Rosa Eva; Parl, Andrea; Eggert, Carola; Novak, Bozidar; Yan, Yu; Yeoh, Karin; Lebar, Maria; Hauger, Barbara; Harbich, Daniela; Schmid, Bianca; Di Giaimo, Rossella; Turck, Christoph W.; Schmidt, Mathias V.; Deussing, Jan M.; Eder, Matthias; Dine, Julien; Theis, Fabian J.; Chen, Alon

doi:10.1016/j.neuron.2022.05.001

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Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2

MPS-Authors

/persons/resource/persons222540

Lopez, Juan Pablo
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262050

Brivio, Elena
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons221997

Karamihalev, Stoyo
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons227188

Kos, Aron
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons263541

De Donno, Carlo
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons265581

Benjamin, Asaf
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons261972

Yang, Huanqing
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons188826

Dick, Alec L. W.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons200349

Stoffel, Rainer
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80324

Flachskamm, Cornelia
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons136556

Ressle, Andrea
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons128467

Roeh, Simone
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons223831

Huettl, Rosa Eva
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons278204

Parl, Andrea
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons226690

Eggert, Carola
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons185107

Novak, Bozidar
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262056

Yan, Yu
RG Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons263188

Yeoh, Karin
RG Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80420

Lebar, Maria
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80355

Hauger, Barbara
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80353

Harbich, Daniela
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons136234

Schmid, Bianca
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222059

Di Giaimo, Rossella
Max Planck Research Group Developmental Neurobiology (Silvia Cappello), Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80561

Turck, Christoph W.
RG Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80514

Schmidt, Mathias V.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80301

Deussing, Jan M.
RG Molecular Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80315

Eder, Matthias
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80306

Dine, Julien
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons129892

Chen, Alon
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Lopez, J. P., Luecken, M. D., Brivio, E., Karamihalev, S., Kos, A., De Donno, C., et al. (2022). Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2. NEURON, 110(14), 2283-2298.e9. doi:10.1016/j.neuron.2022.05.001.

Cite as: https://hdl.handle.net/21.11116/0000-000A-FBB7-D

Abstract

A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified cell-type-specific transcrip-tional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electro-physiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine???s antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical an-tidepressants, such as escitalopram. These findings significantly advance our understanding of the mecha-nisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.