A cell type-specific mechanism driving the rapid antidepressant effects of transcranial magnetic stimulation

Michael W Gongwer; Alex Qi; Alexander S Enos; Sophia A Rueda Mora; Sabahaddin Taha Solakoğlu; Russell N Ahmed; Cassandra B Klune; Meelan Shari; Adrienne Q Kashay; Owen H Williams; Aliza Hacking; Jack P Riley; Gary A Wilke; Yihong Yang; Hanbing Lu; Andrew F Leuchter; Laura A DeNardo; Scott A Wilke

doi:10.1016/j.cell.2025.12.040

A cell type-specific mechanism driving the rapid antidepressant effects of transcranial magnetic stimulation

Cell. 2026 May 14;189(10):3052-3070.e13. doi: 10.1016/j.cell.2025.12.040. Epub 2026 May 7.

Authors

Michael W Gongwer¹, Alex Qi², Alexander S Enos³, Sophia A Rueda Mora³, Sabahaddin Taha Solakoğlu², Russell N Ahmed², Cassandra B Klune³, Meelan Shari³, Adrienne Q Kashay², Owen H Williams³, Aliza Hacking³, Jack P Riley³, Gary A Wilke⁴, Yihong Yang⁵, Hanbing Lu⁵, Andrew F Leuchter², Laura A DeNardo⁶, Scott A Wilke⁷

Affiliations

¹ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Neuroscience Interdepartmental Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, Neuromodulation Division, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Mischief Mazes, LLC, Bellevue, WA 98007, USA.
⁵ Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
⁶ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: ldenardo@ucla.edu.
⁷ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry, Neuromodulation Division, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: swilke@mednet.ucla.edu.

PMID: 42102816
DOI: 10.1016/j.cell.2025.12.040

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is poorly understood. We developed a mouse model of rTMS with superior clinical face validity and investigated the neural mechanism by which accelerated intermittent theta burst stimulation (aiTBS), the first rapid-acting rTMS antidepressant protocol, reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns of neural activity in intratelencephalic (IT) and pyramidal tract (PT) projection neurons in dorsomedial prefrontal cortex (dmPFC). However, only IT neurons exhibited persistently increased activity during both aiTBS and subsequent depression-related behaviors. aiTBS reversed stress-related loss of dendritic spines on IT, but not PT neurons, further demonstrating cell type-specific effects of stimulation. Chemogenetically inhibiting dmPFC IT, but not PT neurons, during rTMS blocked the antidepressant-like behavioral effects of aiTBS. Thus, we demonstrate a prefrontal mechanism linking rapid aiTBS-driven therapeutic effects to cell type-specific circuit plasticity.

Keywords: TMS; brain stimulation; cell types; depression; iTBS; intermittent theta burst; intratelencephalic; neural circuits; prefrontal cortex; transcranial magnetic stimulation.

MeSH terms

Animals
Behavior, Animal
Depression* / therapy
Disease Models, Animal
Male
Mice
Mice, Inbred C57BL
Neuronal Plasticity
Neurons / physiology
Prefrontal Cortex / cytology
Transcranial Magnetic Stimulation* / methods