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Peer-reviewedCC BY 4.0Experimental & Molecular Medicine

Drp1 in M1 layer V GABAergic neurons orchestrates rTMS-mediated motor restoration and analgesia after spinal cord injury

  • Xiaolong Sun1,2
  • Rui Zhao1,2,3
  • Kunlong Zhang1,4
  • Xingxing Feng1
  • Xin Zhang1
  • Xinjiang Yang1,2,3
  • Zhenzhen Li3
  • Ke Tian1
  • Xin Kang1,3
  • Xiaodong Lin1
  • Ming Gao1
  • Xu Hu1
5 more authors
  • Yixing Lu1
  • Ying Liang5
  • Ceng Luo3
  • Yayun Wang4
  • Hua Yuan1
5 affiliations
  1. 1Department of Rehabilitation Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China
  2. 2Military Medical Innovation Center, Fourth Military Medical University, Xi’an, China
  3. 3Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an, China
  4. 4Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Basic Medicine Science Education, Fourth Military Medical University, Xi’an, China
  5. 5Department of Health Statistics, Fourth Military Medical University, Xi’an, China
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Abstract

Spinal cord injury (SCI) leads to chronic motor and sensory deficits, with progressive secondary neurodegeneration posing a major therapeutic challenge. Although high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the primary motor cortex (M1) shows therapeutic potential, its underlying cellular mechanisms remain poorly understood. This translational study first demonstrated that HF-rTMS concurrently improved motor function and alleviated neuropathic pain in retrospective clinical cohorts and a validated murine SCI model. To decipher the supraspinal mechanism, we used an integrated approach combining behavioral analyses, transmission electron microscopy and single-nucleus RNA sequencing. Transcriptomics revealed that HF-rTMS specifically rescued SCI-induced disruptions in oxidative phosphorylation and mitochondrial energy metabolism pathways within M1 GABAergic neurons. Here we pinpointed a key molecular lesion: SCI selectively downregulated the mitochondrial fission regulator Drp1 in M1 layer V GABAergic neurons, leading to dysfunctional mitochondrial dynamics and bioenergetic deficits. HF-rTMS restored Drp1 levels and mitochondrial ultrastructure specifically in M1 but not in the primary somatosensory cortex, underscoring its region-selective action. Most importantly, functional causality was established: Drp1 overexpression in M1 GABAergic neurons mimicked the therapeutic benefits of HF-rTMS, whereas Drp1 knockdown or its pharmacological inhibition completely abolished these effects. Our findings establish impaired mitochondrial dynamics in a specific cortical microcircuit as a convergent driver of multisystem deficits post SCI, and identify Drp1 as a pivotal molecular target of HF-rTMS. This work provides a novel mechanistic foundation for Drp1-directed precision therapies, highlighting the potential of rescuing cortical mitochondrial bioenergetics to halt progressive secondary damage and improve functional recovery after central nervous system injury.

This study demonstrates that high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) alleviates motor dysfunction and neuropathic pain after spinal cord injury (SCI). We show that HF-rTMS acts by upregulating the mitochondrial fission protein Drp1 specifically in layer V GABAergic neurons of the primary motor cortex. This restoration of Drp1 rescues impaired mitochondrial dynamics, normalizes associated proteins (VDAC-1 and Tom20) and recovers cellular energy (ATP) production. Consequently, rTMS reverses SCI-induced mitochondrial pathology, leading to substantial functional recovery. The therapeutic effect is dependent on Drp1, as its inhibition abolishes the benefits of HF-rTMS. Our findings reveal a precise neuromodulation mechanism targeting cortical mitochondrial homeostasis for treating SCI comorbidity.

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Cite

BibTeXRIS
BibTeX
@article{sun2026drp1,
  title = {{Drp1 in M1 layer V GABAergic neurons orchestrates rTMS-mediated motor restoration and analgesia after spinal cord injury}},
  author = {Xiaolong Sun and Rui Zhao and Kunlong Zhang and Xingxing Feng and Xin Zhang and Xinjiang Yang and Zhenzhen Li and Ke Tian and Xin Kang and Xiaodong Lin and Ming Gao and Xu Hu and Yixing Lu and Ying Liang and Ceng Luo and Yayun Wang and Hua Yuan},
  journal = {Experimental \& Molecular Medicine},
  year = {2026},
  month = oct,
  doi = {10.1038/s12276-026-01857-2},
  url = {https://doi.org/10.1038/s12276-026-01857-2},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Drp1 in M1 layer V GABAergic neurons orchestrates rTMS-mediated motor restoration and analgesia after spinal cord injury
AU  - Xiaolong Sun
AU  - Rui Zhao
AU  - Kunlong Zhang
AU  - Xingxing Feng
AU  - Xin Zhang
AU  - Xinjiang Yang
AU  - Zhenzhen Li
AU  - Ke Tian
AU  - Xin Kang
AU  - Xiaodong Lin
AU  - Ming Gao
AU  - Xu Hu
AU  - Yixing Lu
AU  - Ying Liang
AU  - Ceng Luo
AU  - Yayun Wang
AU  - Hua Yuan
PY  - 2026
DA  - 2026/10/05
JO  - Experimental & Molecular Medicine
DO  - 10.1038/s12276-026-01857-2
UR  - https://doi.org/10.1038/s12276-026-01857-2
AB  - Spinal cord injury (SCI) leads to chronic motor and sensory deficits, with progressive secondary neurodegeneration posing a major therapeutic challenge. Although high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the primary motor cortex (M1) shows therapeutic potential, its underlying cellular mechanisms remain poorly understood. This translational study first demonstrated that HF-rTMS concurrently improved motor function and alleviated neuropathic pain in retrospective clinical cohorts and a validated murine SCI model. To decipher the supraspinal mechanism, we used an integrated approach combining behavioral analyses, transmission electron microscopy and single-nucleus RNA sequencing. Transcriptomics revealed that HF-rTMS specifically rescued SCI-induced disruptions in oxidative phosphorylation and mitochondrial energy metabolism pathways within M1 GABAergic neurons. Here we pinpointed a key molecular lesion: SCI selectively downregulated the mitochondrial fission regulator Drp1 in M1 layer V GABAergic neurons, leading to dysfunctional mitochondrial dynamics and bioenergetic deficits. HF-rTMS restored Drp1 levels and mitochondrial ultrastructure specifically in M1 but not in the primary somatosensory cortex, underscoring its region-selective action. Most importantly, functional causality was established: Drp1 overexpression in M1 GABAergic neurons mimicked the therapeutic benefits of HF-rTMS, whereas Drp1 knockdown or its pharmacological inhibition completely abolished these effects. Our findings establish impaired mitochondrial dynamics in a specific cortical microcircuit as a convergent driver of multisystem deficits post SCI, and identify Drp1 as a pivotal molecular target of HF-rTMS. This work provides a novel mechanistic foundation for Drp1-directed precision therapies, highlighting the potential of rescuing cortical mitochondrial bioenergetics to halt progressive secondary damage and improve functional recovery after central nervous system injury.  This study demonstrates that high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) alleviates motor dysfunction and neuropathic pain after spinal cord injury (SCI). We show that HF-rTMS acts by upregulating the mitochondrial fission protein Drp1 specifically in layer V GABAergic neurons of the primary motor cortex. This restoration of Drp1 rescues impaired mitochondrial dynamics, normalizes associated proteins (VDAC-1 and Tom20) and recovers cellular energy (ATP) production. Consequently, rTMS reverses SCI-induced mitochondrial pathology, leading to substantial functional recovery. The therapeutic effect is dependent on Drp1, as its inhibition abolishes the benefits of HF-rTMS. Our findings reveal a precise neuromodulation mechanism targeting cortical mitochondrial homeostasis for treating SCI comorbidity.
SN  - 1226-3613
SN  - 2092-6413
ER  -