High-frequency repetitive transcranial magnetic stimulation upregulates BDNF expression and promotes synaptogenesis in mouse models of Parkinson's disease

Synaptic dysfunction exists before symptoms occur in Parkinson's disease, and restoring synaptic function as a promising therapeutic approach. Brain-derived neurotrophic factor serves as a key neuroregulatory factor in regulating synaptic function. Studies have shown that the protein levels of brain-derived neurotrophic factor is low in Parkinson's disease mice. However, repetitive transcranial magnetic stimulation (rTMS) can mitigate this decline. We explored the protective role of rTMS on brain-derived neurotrophic factor and synaptic function in a mouse Parkinson's disease model. The bioinformatics analysis further confirmed the regulation of synaptic function. Behavioral tests, Western blot tests, and immunofluorescence were performed. In 1-methyl-4-phenyl1,2,3, 6-tetrahydropyridine mouse model, low, medium, and high frequency magnetic stimulation were used at the same time, and we found that only the high frequency group improved dopaminergic neuron loss and the expression of brain-derived neurotrophic factor. Meanwhile, high frequency rTMS treatment alleviated motor dysfunction by alleviating the loss of dopaminergic neurons within the substantia nigra. In addition, high frequency treatment induced the phosphorylation of Ca2+/calmodulin-dependent protein kinase II and cAMP response element-binding protein, but the total protein level did not change significantly. After further use of KN93 antagonism, it was observed that P- Ca2+/calmodulin-dependent protein kinase II, P-cAMP response element-binding protein, brain-derived neurotrophic factor, and synapse-related protein expression were decreased, and rTMS protection was no longer effective. Therefore, rTMS therapy may upregulate brain-derived neurotrophic factor through the Ca2+/calmodulin-dependent protein kinase II-cAMP response element-binding protein pathway, improve synaptic function, and protect dopaminergic neurons, thereby enhancing motor function.

Brain-derived neurotrophic factor; Ca2+/calmodulin-dependent protein kinase II; Synapse; cAMP response element-binding protein; repetitive transcranial magnetic stimulation, Parkinson’s disease.