Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition
Steven F. Grieco, Yu-yan Cheng, H. Eldar-Finkelman, R. Jope, Eléonore Beurel
Progress in Neuro-Psychopharmacology and Biological Psychiatry August 16, 2016 DOI: 10.1016/j.pnpbp.2016.08.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine IGF2 siRNA |
| Dose | 10 mg/kg |
| Topics | Esketamine Ketamine |
| Key points | Ketamine increases hippocampal IGF2 expression via GSK3 inhibition, and IGF2 is required for ketamine's antidepressant effect and may confer resilience to depression-like behavior. |
Abstract
ABSTRACT An antidepressant dose of the rapidly‐acting ketamine inhibits glycogen synthase kinase‐3 (GSK3) in mouse hippocampus, and this inhibition is required for the antidepressant effect of ketamine in learned helplessness depression‐like behavior. Here we report that treatment with an antidepressant dose of ketamine (10 mg/kg) increased expression of insulin‐like growth factor 2 (IGF2) in mouse hippocampus, an effect that required ketamine‐induced inhibition of GSK3. Ketamine also inhibited hippocampal GSK3 and increased expression of hippocampal IGF2 in mice when administered after the induction of learned helplessness. Treatment with the specific GSK3 inhibitor L803‐mts was sufficient to up‐regulate hippocampal IGF2 expression. Administration of IGF2 siRNA reduced ketamine's antidepressant effect in the learned helplessness paradigm. Mice subjected to the learned helplessness paradigm were separated into two groups, those that were resilient (non‐depressed) and those that were susceptible (depressed). Non‐depressed resilient mice displayed higher expression of IGF2 than susceptible mice. These results indicate that IGF2 contributes to ketamine's antidepressant effect and that IGF2 may confer resilience to depression‐like behavior. HIGHLIGHTSAn antidepressant dose of ketamine up‐regulates IGF2 in mouse hippocampusGSK3 inhibition is necessary and sufficient for up‐regulation of IGF2Ketamine inhibits activated GSK3 and increases IGF2 expression in depressed miceIGF siRNA blocks ketamine's antidepressant efficacy in learned helplessnessIGF2 levels may differentiate resilient and susceptible mice to learned helplessness
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 7
- Ketamine as a Rapid-Acting Antidepressant: A Scoping Review of Mechanisms and Efficacy in Treatment-Resistant Depression. Psychopathology March 27, 2026
- Time-Dependent Effects of Rapid-Acting Antidepressants in iPSC-Derived Neurons from Treatment-Resistant Depression and Healthy Volunteers. Research Square February 12, 2026
- Novel and emerging anesthetic drugs for the treatments of major depression: a comprehensive review of efficacy, mechanism, and outlook. Frontiers in Psychiatry 2025
- Role of neurotrophic and growth factors in the rapid and sustained antidepressant actions of ketamine. Neuropharmacology November 17, 2022
- The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity Frontiers in Psychiatry April 25, 2022
and 2 more in the library
Cites 10
- 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
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
- Glutamate Receptor Antagonists as Fast-Acting Therapeutic Alternatives for the Treatment of Depression: Ketamine and Other Compounds The Annual Review of Pharmacology and Toxicology January 6, 2014
- Antidepressant mechanism of ketamine: perspective from preclinical studies Frontiers in Neuroscience July 21, 2015
and 5 more in the library