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氯胺酮诱导人iPSC来源神经元的突触与单胺能重塑

Ketamine induces synaptic and monoaminergic remodeling in human iPSC-derived neurons

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一项发表于Translational Psychiatry的研究显示，氯胺酮（1 µM，处理72小时）可显著增加人iPSC来源前脑神经元突触后支架蛋白PSD-95的突触定位，并选择性调控Akt通路，但不改变BDNF蛋白水平或MAPK激活。

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Translational Psychiatry (2026) Cite this article

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Abstract

Major depressive disorder (MDD) is a leading cause of global disability, and a substantial proportion of patients develop treatment-resistant depression (TRD), highlighting the urgent need for mechanistically novel and fast-acting antidepressants. Ketamine has emerged as a paradigm-shifting therapy due to its rapid and robust antidepressant effects, yet its molecular mechanisms in human neurons remain incompletely understood. Here, we investigated the cellular and transcriptomic effects of ketamine in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons. Neuronal cultures were treated with ketamine (1 µM) for 72 h and analyzed using immunocytochemistry, western blotting, and RNA sequencing. Ketamine treatment did not alter gross neuronal morphology or presynaptic organization but significantly increased synaptic localization of the postsynaptic scaffolding protein PSD-95, suggesting molecular changes associated with synaptic remodeling. At the signaling level, ketamine selectively modulated the Akt pathway without inducing changes in BDNF protein levels or MAPK activation, and without broadly altering excitatory or inhibitory synaptic protein expression. Transcriptomic profiling revealed 604 differentially expressed genes, with significant enrichment of pathways related to serotonergic and dopaminergic neurotransmission. Notably, ketamine upregulated genes involved in monoamine synthesis and signaling, including DDC and DRD1, while downregulating genes associated with GPCR ligand binding and neurotransmitter transport. SynGO analysis further identified selective regulation of synapse-associated genes, predominantly affecting presynaptic and neurotransmitter uptake mechanisms. Together, these findings indicate that ketamine induces molecular and transcriptional changes in human neurons that are consistent with synaptic remodeling and with activation of transcriptional programs enriched for monoaminergic signaling pathways. This hiPSC-based model provides a platform to investigate the molecular responses of human neurons to ketamine and to explore patient-specific mechanisms in future studies.

Acknowledgements

We thank Prof. Laura Musazzi (University of Milano-Bicocca) for kindly providing some of the reagents used in this study and Alessia Stefanoni for her contribution to the preliminary experiments.

Funding

This work was supported by Italian Cariplo Foundation (grant 2019-3396) to C.S. and L.C., by the Jerome Lejeune (project #1638) and by the Telethon Fondazione Onlus (GRM22T1610) to C.S.

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Author notes

  1. These authors contributed equally: Jessica Pagano, Eleonora Mangano.

Authors and Affiliations

  1. CNR Institute of Neuroscience, Milano, 20854, Vedano al Lambro, Italy

    Jessica Pagano, Sofia Eminente, Matteo Colombo & Carlo Sala

  2. CNR Institute for Biomedical Technologies, 20054, Segrate, Italy

    Eleonora Mangano & Roberta Bordoni

  3. Department of Mental Health, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS) San Gerardo dei Tintori, 20090, Monza, Italy

    Matteo Marcatili

  4. Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University, 81101, Bratislava, Slovakia

    Michaela Krivosova

  5. Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, 20122, Milan, Italy

    Viviana Tritto

  6. Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany

    Tobias M. Boeckers

  7. Ulm Site, DZNE, Ulm, Germany

    Tobias M. Boeckers

  8. Laboratory of Stem Cell Biology, Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123, Trento, Italy

    Luciano Conti

  9. Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS), San Gerardo dei Tintori, 20090, Monza, Italy

    Carlo Sala

Authors

  1. Jessica Pagano
  2. Eleonora Mangano
  3. Sofia Eminente
  4. Matteo Marcatili
  5. Michaela Krivosova
  6. Matteo Colombo
  7. Viviana Tritto
  8. Roberta Bordoni
  9. Tobias M. Boeckers
  10. Luciano Conti
  11. Carlo Sala

Corresponding author

Correspondence to Carlo Sala.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics

The study was performed using previously established human induced pluripotent stem cell (iPSC) lines [14, 33]. No new human samples were collected, and no participants were recruited for this study. Therefore, no additional ethical approval was required for the experiments reported in this manuscript.

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Cite this article

Pagano, J., Mangano, E., Eminente, S. et al. Ketamine induces synaptic and monoaminergic remodeling in human iPSC-derived neurons. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-04525-1

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  • Received: 11 March 2026

  • Revised: 09 September 2026

  • Accepted: 01 October 2026

  • Published: 16 October 2026

  • DOI: https://doi.org/10.1038/s41398-026-04525-1

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