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

Key findings from this study

This research indicates that:

• Single transient low-frequency low-intensity electrical stimulation induces robust dendritic and somatic remodeling in human dopaminergic neurons comparable to ketamine-like plasticity
• Electrical stimulation-induced plasticity requires L-type voltage-gated calcium channels, BDNF-TrkB signaling, and mTOR pathway activation
• Electrical stimulation fully reverses cortisol-induced neuronal atrophy, suggesting capacity to rescue stress hormone-related impairments in vitro

Overview

Single transient low-frequency low-intensity electrical stimulation applied to human iPSC-derived dopaminergic neurons produces structural and molecular plasticity comparable to ketamine, operating through calcium-dependent BDNF-TrkB-ERK-mTOR signaling and dopamine D3 auto-receptor engagement. The study evaluated whether brief electrical stimulation can induce rapid plasticity changes and reverse glucocorticoid-induced neuronal impairments in vitro.

Methods and approach

iPSC-derived mesencephalic dopaminergic neurons underwent single 1-hour low-frequency low-intensity electrical stimulation at 4 mA using a custom culture-compatible stimulator. Structural plasticity quantification occurred three days post-stimulation via computer-assisted morphometry. Pharmacological blockers targeting L-type voltage-gated calcium channels, TrkB, and mTOR assessed mechanistic contributions. Quantitative PCR and Western blot analyses measured calcium influx, phosphorylation of ERK and p70-S6K, BDNF signaling, and dopamine D3 auto-receptor expression. Cortisol-treated neurons assessed rescue of stress hormone-induced impairments.

Results

A single 1-hour electrical stimulation session substantially increased maximal dendrite length, primary dendrite number, and soma area, matching effects of 1 micromolar ketamine. Electrical stimulation rapidly enhanced ERK and p70-S6K phosphorylation. Blocking L-type voltage-gated calcium channels, TrkB, or mTOR prevented structural remodeling, indicating these elements mediate plasticity responses. Electrical stimulation upregulated dopamine D3 auto-receptor messenger RNA, and antagonizing D3 receptors attenuated the induced plasticity. In cortisol-treated neurons, electrical stimulation fully reversed dendritic hypotrophy and soma shrinkage, restoring morphological parameters to control levels.

Implications

Brief electrical stimulation of dopaminergic neurons generates long-lasting structural and molecular changes comparable to rapid-acting antidepressants despite the absence of pharmacological intervention. The ketamine-like effects and glucocorticoid reversal suggest electrical stimulation engages fundamental plasticity mechanisms relevant to depression pathophysiology and treatment resistance. These findings support developing electrical stimulation-based neuromodulation therapies targeting dopaminergic circuitry in major depressive disorder.

Scope and limitations

This summary is based on the study abstract and available metadata. It does not include a full analysis of the complete paper, supplementary materials, or underlying datasets unless explicitly stated. Findings should be interpreted in the context of the original publication.