Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy.
Allie J Widman, Lori L McMahon
Proceedings of the National Academy of Sciences March 27, 2018 DOI: 10.1073/pnas.1718883115 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro electrophysiology study Peer reviewed |
|---|---|
| Population | Acute slices of dorsal hippocampus from adult male Sprague-Dawley rats |
| Interventions | Ketamine GLYX-13 (rapastinel) Ro 25-6981 Scopolamine |
| Topics | Esketamine Ketamine |
| Keywords | Gabaergic transmission Disinhibition Excitation/inhibition balance Hippocampal networks Major depression |
| Key points | Low-dose ketamine, GLYX-13, and scopolamine reduced inhibitory input onto hippocampal pyramidal cells and increased synaptically driven pyramidal cell excitability, whereas Ro 25-6981 increased inhibitory transmission strength and did not change excitability. The authors argue this decrease in the inhibition/excitation balance supports disinhibition as a common mechanism among antagonists with rapid antidepressant properties. |
Abstract
Low-dose ketamine, an open-channel N-methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated. Using in vitro electrophysiology in acute slices of dorsal hippocampus from adult male Sprague-Dawley rats, we examined the immediate effects of a clinically relevant concentration of ketamine to directly test the disinhibition hypothesis. As a mechanistic comparison, we also tested the effects of the glycine site NMDAR partial agonist/antagonist GLYX-13 (rapastinel), the GluN2B subunit-selective NMDAR antagonist Ro 25-6981, and the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine. Low-dose ketamine, GLYX-13, and scopolamine reduced inhibitory input onto pyramidal cells and increased synaptically driven pyramidal cell excitability measured at the single-cell and population levels. Conversely, Ro 25-6981 increased the strength of inhibitory transmission and did not change pyramidal cell excitability. These results show a decrease in the inhibition/excitation balance that supports disinhibition as a common mechanism shared among those antagonists with rapid antidepressant properties. These data suggest that pyramidal cell disinhibition downstream of NMDAR antagonism could serve as a possible biomarker for the efficacy of rapid antidepressant therapy.
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 67
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide F1000Research May 24, 2018
- Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines Nature Communications June 3, 2019
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
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Cites 18
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- 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 Journal of Neuroscience April 15, 1997
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 13 more in the library