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 transcriptional 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, electrophysiological, 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 antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.
Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2 / Lopez, Juan Pablo; Lücken, 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; Holzapfel, 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. - In: NEURON. - ISSN 0896-6273. - 110:14(2022), pp. 2283-2298.e9. [10.1016/j.neuron.2022.05.001]
Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2
Di Giaimo, Rossella;
2022
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 transcriptional 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, electrophysiological, 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 antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.File | Dimensione | Formato | |
---|---|---|---|
1-s2.0-S0896627322004093-main.pdf
solo utenti autorizzati
Tipologia:
Versione Editoriale (PDF)
Licenza:
Copyright dell'editore
Dimensione
5.43 MB
Formato
Adobe PDF
|
5.43 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.