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) via Semantic Scholar
Summary
AI-generated from the abstractKetamine, an NMDA receptor antagonist, shows rapid and lasting antidepressant effects even in treatment-resistant depression, but its mechanism is unclear. Using human stem cell-derived neural progenitor cells (NPCs), ketamine increased cell proliferation independently of the NMDA receptor. Transcriptome analysis revealed upregulation of IGF2 and p11, proteins linked to depression, 24 hours after treatment. Ketamine (1 µM) boosted cAMP signaling within 15 minutes and proliferation; blocking PKA reduced IGF2 expression. In mice, ketamine (15 mg/kg) confirmed ERK1/2 phosphorylation in the hippocampus. Ketamine likely promotes NPC proliferation through cAMP-IGF2 signaling.
Study at a glance
| 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) |
| Keywords | Medicine Chemistry Biology |
| Key finding | 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.