Single transient exposure to low-frequency low-intensity electrical stimulation produces ketamine-like effects in human iPSC-derived dopaminergic neurons via Ca2+-dependent BDNF and mTOR signaling.
G. S. Marcotto, M. Borghetti, J. Bitraj, Laura Cavalleri, M. Serpelloni, Michele Zoli, Maurizio Memo, E. Sardini, Ginetta Collo
Neuropharmacology August 1, 2026 DOI: 10.1016/j.neuropharm.2026.110964 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Human induced pluripotent stem cell (iPSC)-derived mesencephalic dopaminergic neurons |
| Dose | 4 mA, 1 hour |
| Duration | Structural plasticity assessed three days after stimulation |
| Measures | computer-assisted morphometry, quantitative PCR, Western blot |
| Topics | Esketamine Ketamine |
| Key findings | A single 1-hour LF-LI ES session at 4 mA induced robust structural plasticity in human dopaminergic neurons, comparable to 1 μM ketamine, and fully reversed cortisol-induced dendritic hypotrophy and soma shrinkage. The effects required L-type calcium channels, TrkB, and mTOR, and were attenuated by dopamine D3 auto-receptor antagonism, suggesting a ketamine-like mechanism. |
Abstract
Electrical stimulation (ES) is emerging as a non-pharmacological neuromodulation strategy, but its direct impact on human dopaminergic neurons and its relationship to rapid-acting antidepressant mechanisms remain unclear. This study aimed to investigate whether brief biphasic low-frequency low-intensity (LF-LI) ES can induce structural and molecular plasticity in human induced pluripotent stem cell (iPSC)-derived mesencephalic dopaminergic neurons, identify the underlying signaling mechanisms, and evaluate its potential to rescue cortisol-induced impairments as in-vitro endocrine model of depression. iPSC-derived dopaminergic neurons were exposed to LF-LI ES using a custom culture-compatible stimulator, and structural plasticity was quantified three days later by computer-assisted morphometry. Pharmacological blockers, quantitative PCR and Western blot analyses were employed to assess calcium influx, brain-derived neurotrophic factor (BDNF)-TrkB-extracellular signal-regulated kinase (ERK)-mTOR signaling, and dopamine D3 auto-receptor roles in mediating LF-LI ES effects. A single 1h LF-LI ES session at 4 mA induced robust increases in maximal dendrite length, primary dendrite number, and soma area, comparable to 1 μM ketamine. LF-LI ES rapidly enhanced ERK and p70-S6K phosphorylation and required L-type voltage-gated calcium channels, TrkB and mTOR, as their inhibition prevented structural remodeling. LF-LI ES increased dopamine D3 auto-receptors mRNA, and its antagonism attenuated LF-LI ES-induced plasticity. In cortisol-treated neurons, LF-LI ES fully reversed dendritic hypotrophy and soma shrinkage. In conclusion, brief LF-LI ES elicits long-lasting, ketamine-like structural and molecular plasticity in human dopaminergic neurons and rescues stress hormone-induced impairments, supporting LF-LI ES-based neuromodulation approaches targeting dopaminergic circuits in major depressive disorder and treatment-resistant depression.
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
Cites 3
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action Cell Reports August 1, 2021