Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines
Farhan Ali, Danielle M. Gerhard, Katherine Sweasy, Santosh Pothula, Christopher Pittenger, Ronald S. Duman, A. Kwan
Nature Communications June 3, 2019 DOI: 10.1038/s41467-019-13809-8 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Awake mice |
| Intervention | subanesthetic ketamine |
| Dose | subanesthetic dose |
| Topics | Esketamine Ketamine |
| Citations | 201 |
| Key findings | Ketamine suppresses SST interneurons in the medial prefrontal cortex, causing dendritic disinhibition and elevated calcium signals in apical dendritic spines of pyramidal neurons. |
Abstract
A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine. The authors show that a subanesthetic dose of ketamine markedly elevate calcium signals in apical dendritic spines in the mouse prefrontal cortex. This effect is driven by a local-circuit mechanism that involves the suppression of somatostatin interneurons leading to dendritic disinhibition.
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 82
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
- Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin ACS Chemical Neuroscience January 11, 2023
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Cites 9
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- 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
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
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