High-Frequency rTMS can Improve Depressive Symptoms by Promoting Mitochondrial Fusion

Depression is a common and highly prevalent disabling mental disorder. Recent clinical data have shown that repetitive transcranial magnetic stimulation (rTMS) effectively improves depressive symptoms. Mitochondrial quality control (MQC) plays a central role in various psychiatric disorders. However, the relationship between the therapeutic mechanisms underlying rTMS and MQC remains unclear. This study aimed to evaluate the therapeutic effect of rTMS on depression and to investigate the relationship between rTMS and MQC.

A depression model was established using chronic unpredictable mild stress (CUMS). The rTMS treatment protocol was administered daily for 4 weeks at a frequency of 10 Hz (17 trains of 4 s each, with 15 s intervals), totaling 1000 pulses per day. Each session involved 10 s of stimulation followed by 50 s of rest and was divided into four groups: control, CUMS, CUMS + 10 Hz rTMS, and fluoxetine (FlX)-treated groups (six mice in each group). In this study, we used the open field test (OFT), tail suspension test (TST), sucrose preference test (SPT), and forced swimming test (FST) to assess depression in mice; immunohistochemical staining to observe changes in the prefrontal cortex (PFC), hippocampal neurons, and glial cells; and transmission electron microscopy to detect changes in mitochondrial morphology in the hippocampus.

Our findings suggest that mitochondrial pre-autophagy increased after treatment (LC3Ⅰ/II, F = 34.31, p < 0.0001; FIS1, F = 6.666, p = 0.0272), hippocampal mitochondrial fusion was enhanced after treatment (NeuN, p < 0.0001; c-Fos, p < 0.001; MFN1, p = 0.0006), and that treatment significantly improved the depression-like behavior of mice in the SPT (p = 0.0024) and FST (p = 0.0025).

The present study demonstrates that rTMS improves depression-like behavior in mice by promoting mitochondrial fusion and enhancing autophagy.