Transcriptional Activation, Deactivation and Rebound Patterns in Cortex, Hippocampus and Amygdala in Response to Ketamine Infusion in Rats
Jenny J. Kim, M. Sapio, Fernando A. Vazquez, D. Maric, Amelia J. Loydpierson, Wen-Ting Ma, Carlos A. Zarate, M. Iadarola, Andrew J Mannes
Frontiers in Molecular Neuroscience May 30, 2022 DOI: 10.3389/fnmol.2022.892345 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Molecular-pharmacological investigation in the rat Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | Ketamine |
| Dose | high dose ketamine, anesthetic concentrations |
| Duration | 1 h, 10 h, and 10 h + 24 h recovery infusions |
| Measures | RNA-Seq, multiplex fluorescent in situ hybridization |
| Topics | Esketamine Ketamine |
| Key points | Ketamine infusion induced a shared transcriptional regulatory network within 1 hour across frontal cortex, hippocampus, and amygdala, involving immediate early genes and the Nrf2 oxidative stress-antioxidant pathway. Longer 10-hour infusions reinforced and strengthened these gene alterations, and 24-hour recovery produced overshoot rather than smooth return to homeostasis, suggesting oscillating plasticity. The authors propose these molecular actions may underlie ketamine's therapeutic attributes. |
Abstract
Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, is a recently revitalized treatment for pain and depression, yet its actions at the molecular level remain incompletely defined. In this molecular-pharmacological investigation in the rat, we used short- and longer-term infusions of high dose ketamine to stimulate neuronal transcription processes. We hypothesized that a progressively stronger modulation of neuronal gene networks would occur over time in cortical and limbic pathways. A continuous intravenous administration paradigm for ketamine was developed in rat consisting of short (1 h) and long duration (10 h, and 10 h + 24 h recovery) infusions of anesthetic concentrations to activate or inhibit gene transcription in a pharmacokinetically controlled fashion. Transcription was measured by RNA-Seq in three brain regions: frontal cortex, hippocampus, and amygdala. Cellular level gene localization was performed with multiplex fluorescent in situ hybridization. Induction of a shared transcriptional regulatory network occurred within 1 h in all three brain regions consisting of (a) genes involved in stimulus-transcription factor coupling that are induced during altered synaptic activity (immediate early genes, IEGs, such as c-Fos, 9–12 significant genes per brain region, p < 0.01 per gene) and (b) the Nrf2 oxidative stress-antioxidant response pathway downstream from glutamate signaling (Nuclear Factor Erythroid-Derived 2-Like 2) containing 12–25 increasing genes (p < 0.01) per brain region. By 10 h of infusion, the acute results were further reinforced and consisted of more and stronger gene alterations reflecting a sustained and accentuated ketamine modulation of regional excitation and plasticity. At the cellular level, in situ hybridization localized up-regulation of the plasticity-associated gene Bdnf, and the transcription factors Nr4a1 and Fos, in cortical layers III and V. After 24 h recovery, we observed overshoot of transcriptional processes rather than a smooth return to homeostasis suggesting an oscillation of plasticity occurs during the transition to a new phase of neuronal regulation. These data elucidate critical molecular regulatory actions during and downstream of ketamine administration that may contribute to the unique drug actions of this anesthetic agent. These molecular investigations point to pathways linked to therapeutically useful attributes of ketamine.
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 3
- Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome. Translational Psychiatry July 25, 2024
- Brain-epigenome wide association study (BEWAS) on the effects of two emerging psychedelics: ketamine & MDMA bioRxiv Preprint Server July 3, 2025
- Ketamine administration reduced conditioned defensive behaviour and upregulated protein expression associated with neuroplasticity in a planarian model of aversive memory reactivation. Progress in neuro-psychopharmacology & biological psychiatry October 17, 2026
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- 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
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
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and 16 more in the library