GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions
Danielle M Gerhard1,2, Santosh Pothula2, Rong-Jian Liu2
1Department of Psychiatry, Weill Cornell Medicine, New York, New York, USA.
The Journal of Clinical Investigation
|November 20, 2019
Summary
Ketamine
Area of Science:
- Neuroscience
- Psychiatry
- Pharmacology
Background:
- Ketamine, an NMDA receptor antagonist, shows rapid antidepressant effects.
- The cellular trigger for ketamine's antidepressant action remains unknown.
- Understanding ketamine's mechanism is crucial for treating mood disorders.
Purpose of the Study:
- Identify the initial cellular trigger for ketamine's antidepressant effects.
- Investigate the role of GluN2B-NMDARs in ketamine's action.
- Explore sex-specific differences in ketamine's mechanism.
Main Methods:
- Cell-specific knockdown/deletion of GluN2B using viral shRNA and conditional mutation.
- Examined effects on GABA and glutamate neurons in the medial prefrontal cortex (mPFC).
- Assessed antidepressant actions and excitatory postsynaptic currents.
Main Results:
- Ketamine's antidepressant effects were blocked by GluN2B knockdown in GABA interneurons (Gad1, Sst, Pvalb).
- Knockdown in glutamate principal neurons did not block ketamine's effects.
- GluN2B deletion in Sst interneurons occluded antidepressant actions and revealed sex-specific differences.
Conclusions:
- GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for ketamine's antidepressant effects.
- Ketamine's rapid antidepressant actions are mediated by these specific interneurons.
- Sex-specific adaptive mechanisms influence ketamine's response via GluN2B modulation.
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