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Brief electrical stimulation produced ketamine-like plasticity in human dopaminergic neurons

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Research area:psychology-neuroscienceneuroscience-neuroengineering

What the study found

A single brief exposure to low-frequency, low-intensity electrical stimulation produced ketamine-like structural and molecular changes in human induced pluripotent stem cell-derived dopaminergic neurons. The study also found that this stimulation reversed cortisol-induced dendritic and cell-body shrinkage in an in-vitro model.

Why the authors say this matters

The authors conclude that these findings support low-frequency, low-intensity electrical stimulation as a neuromodulation approach targeting dopaminergic circuits in major depressive disorder and treatment-resistant depression. The study suggests this may be relevant because it produced effects similar to ketamine, a rapid-acting antidepressant.

What the researchers tested

The researchers exposed human iPSC-derived mesencephalic dopaminergic neurons to brief biphasic low-frequency, low-intensity electrical stimulation using a custom culture-compatible stimulator. They then measured structural plasticity three days later and used pharmacological blockers, quantitative PCR, and Western blot analyses to examine calcium influx, BDNF-TrkB-ERK-mTOR signaling, and dopamine D3 auto-receptor involvement. They also tested whether the stimulation could rescue cortisol-induced impairments in an in-vitro endocrine model of depression.

What worked and what didn't

A single 1-hour stimulation session at 4 mA increased maximal dendrite length, primary dendrite number, and soma area, with effects described as comparable to 1 μM ketamine. The stimulation rapidly increased ERK and p70-S6K phosphorylation, and blocking L-type voltage-gated calcium channels, TrkB, or mTOR prevented the structural remodeling. Dopamine D3 auto-receptor mRNA increased, and antagonizing this receptor attenuated the stimulation-induced plasticity; in cortisol-treated neurons, the stimulation fully reversed dendritic hypotrophy and soma shrinkage.

What to keep in mind

The study was done in human iPSC-derived neurons in vitro, so the findings are limited to this experimental model. The abstract does not describe clinical testing, long-term outcomes beyond the measured period, or additional limitations.

Key points

  • A single 1-hour low-frequency, low-intensity electrical stimulation session increased dendrite length, dendrite number, and soma area in human dopaminergic neurons.
  • The stimulation effects were described as comparable to 1 μM ketamine.
  • Blocking L-type voltage-gated calcium channels, TrkB, or mTOR prevented the structural changes.
  • Dopamine D3 auto-receptor antagonism reduced the stimulation-induced plasticity.
  • The stimulation reversed cortisol-induced dendritic hypotrophy and soma shrinkage in vitro.

Disclosure

Research title:
Brief electrical stimulation produced ketamine-like plasticity in human dopaminergic neurons
Authors:
Giulia Sofia Marcotto, Michela Borghetti, Jonida Bitraj, Laura Cavalleri, Mauro Serpelloni, Michele Zoli, Maurizio Memo, Emilio Sardini, Ginetta Collo
Institutions:
University of Brescia, University of Brescia, University of Brescia, University of Brescia, University of Brescia, University of Brescia, University of Brescia, University of Brescia, University of Modena and Reggio Emilia
Publication date:
2026-04-05
DOI:
10.1016/j.neuropharm.2026.110964
OpenAlex record:
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AI provenance: This post was generated by gpt-5.4-mini (OpenAI). The original authors did not write or review this post.

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