Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor
Alessandra Grossert, N. Mehrjardi, S. Bailey, M. Lindsay, J. Hescheler, T. Šarić, N. Teusch
Cells September 24, 2019 DOI: 10.3390/cells8101139 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and in vivo study Peer reviewed |
|---|---|
| Population | Human iPSC-derived neural progenitor cells and C57BL/6 mice |
| Intervention | Ketamine |
| Dose | 1 µM (in vitro); 15 mg/kg (in vivo) |
| Topics | Esketamine Ketamine |
| Key points | Ketamine promotes proliferation of neural progenitor cells through cAMP-IGF2 signaling, independent of NMDA receptor antagonism. |
Abstract
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of our study was to investigate the molecular mechanism of ketamine at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). Notably, ketamine increased the proliferation of NPCs independent of the NMDA receptor, while transcriptome analysis revealed significant upregulation of insulin-like growth factor 2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 h after ketamine treatment. Ketamine (1 µM) was able to increase cyclic adenosine monophosphate (cAMP) signaling in NPCs within 15 min and cell proliferation, while ketamine-induced IGF2 expression was reduced after PKA inhibition with cAMPS-Rp. Furthermore, 24 h post-administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes the proliferation of NPCs presumably by involving cAMP-IGF2 signaling.
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 5
- The Effect of Ketamine on the Immune System in Patients with Treatment-Resistant Depression International Journal of Molecular Sciences August 1, 2025
- Effect of ketamine and esketamine on RNA expression and its relevance for depression: a systematic review. Pharmacological Research July 31, 2025
- 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
- The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity Frontiers in Psychiatry April 25, 2022
Cites 11
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- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Ketamine: NMDA Receptors and Beyond Journal of Neuroscience November 2, 2016
- Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit Molecular Psychiatry November 21, 2017
- Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model Translational Psychiatry February 23, 2016
and 6 more in the library