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

Abstract

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.

The authors' abstract, as published at the source. Experimental & Molecular Medicine, 2026 · DOI ↗