Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor

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.

The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity

“…Decreased levels of a protein upstream of GSK-3, called insulin-like growth factor 2 (IGF2), has previously been implicated in rodent models of depression, with artificial induction of IGF2 expression having protective effects against depressive-like behaviors ( 156 ). IGF2 is upregulated with ketamine in vivo and in vitro ( 150 , 157 )—and this requires the inhibition of GSK-3 as well ( 150 ). Knocking out IGF2 reduces ketamine’s behavioral antidepressant effect, and mice resilient to induced depression show higher amounts of IGF2 than mice that were susceptible to depression paradigms ( 150 ).…”

Activation of Wnt/β‐catenin signalling and HIF1α stabilisation alters pluripotency and differentiation/proliferation properties of human‐induced pluripotent stem cells

“…hiPS cell line K3(Si‐Tayeb et al., 2010), IMR90 (Grossert et al., 2019) and BJ2 were routinely cultured on Matrigel (BD, Biosciences) in E8 medium (Gibco) at 37°C with 5% CO 2 . For cell differentiation, the hiPSCs were treated by 12 μM CHIR99021 (Selleckchem) for 48 h.…”

Is Adult Hippocampal Neurogenesis Really Relevant for the Treatment of Psychiatric Disorders?

“…However, a recent study found an increase in the densities of neuronal progenitors and newborn GCs in the hippocampal ventral region, together with an increase of expression of specific NMDA and AMPA subunits and mammalian target of rapamycin (mTOR) phosphorylation [ 87 ]. In addition, Grossert et al [ 88 ], through an in vitro model based on human induced pluripotent stem cells (iPSCs), determined an increase of proliferation of NPCs induced by ketamine, where 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.…”