Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.
Manoela V. Fogaça, Fernanda Daher, Marina R. Picciotto
Neuropsychopharmacology March 1, 2025 DOI: 10.1038/s41386-024-02002-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with photometry recordings and chemogenetic approaches in mice Peer reviewed |
|---|---|
| Population | Gad1-Cre mice |
| Intervention | Ketamine |
| Dose | low doses |
| Duration | 24 h and 72 h post-treatment |
| Topics | Ketamine Esketamine |
| Keywords | Antidepressants Brain chemistry Mental health |
| Citations | 22 |
| Key findings | Time-dependent modulation of GABAergic activity in the medial prefrontal cortex is required for the sustained antidepressant-like effects of ketamine. |
Abstract
Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, 60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 11
- Cortical Mechanisms Contributing to Ketamine-Induced Dissociation The Neuroscientist December 26, 2025
- Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets. Cell April 30, 2026
- Cell-type specific transcriptional modulation by psilocybin induces sustained plasticity in mouse medial prefrontal cortex bioRxiv (Cold Spring Harbor Laboratory) January 8, 2025
- Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review. Journal of Affective Disorders May 6, 2026
- Negative allosteric modulation of α5-GABA A receptors engages dynamic cortical glutamatergic and GABAergic mechanisms underlying adaptive behavior in mice. bioRxiv : the preprint server for biology January 16, 2026
and 6 more in the library
Cites 9
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2 R ,6 R )-hydroxynorketamine Proceedings of the National Academy of Sciences December 17, 2018
- A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice eNeuro 2017
and 4 more in the library