Abstract
Repetitive transcranial magnetic stimulation (rTMS) can be used in various neurological disorders. However, neurobiological mechanism of rTMS is not well known. Therefore, in this study, we examined the global gene expression patterns depending on different frequencies of repetitive magnetic stimulation (rMS) in both undifferentiated and differentiated Neuro-2a cells to generate a comprehensive view of the biological mechanisms. The Neuro-2a cells were randomly divided into three groups—the sham (no active stimulation) group, the low-frequency (0.5 Hz stimulation) group, and high-frequency (10 Hz stimulation) group—and were stimulated 10 min for 3 days. The low- and high-frequency groups of rMS on Neuro-2a cells were characterized by transcriptome array. Differentially expressed genes were analyzed using the Database of Annotation Visualization and Integrated Discovery program, which yielded a Kyoto Encyclopedia of Genes and Genomes pathway. Amphetamine addiction pathway, circadian entrainment pathway, long-term potentiation (LTP) pathway, neurotrophin signaling pathway, prolactin signaling pathway, and cholinergic synapse pathway were significantly enriched in high-frequency group compared with low-frequency group. Among these pathways, LTP pathway is relevant to rMS, thus the genes that were involved in LTP pathway were validated by quantitative real-time polymerase chain reaction and western blotting. The expression of glutamate ionotropic receptor N-methyl d-aspartate 1, calmodulin-dependent protein kinase II (CaMKII) δ, and CaMKIIα was increased, and the expression of CaMKIIγ was decreased in high-frequency group. These genes can activate the calcium (Ca2+)–CaMKII–cAMP-response element-binding protein (CREB) pathway. Furthermore, high-frequency rMS induced phosphorylation of CREB, brain-derived neurotrophic factor (BDNF) transcription via activation of Ca2+–CaMKII–CREB pathway. In conclusion, high-frequency rMS enhances the expression of BDNF by activating Ca2+–CaMKII–CREB pathway in the Neuro-2a cells. These findings may help clarify further therapeutic mechanisms of rTMS.
Highlights
Transcranial magnetic stimulation (TMS) is a non-invasive tool that allows electrical stimulation of the nervous system and could be an ideal treatment tool due to its ability to modify brain plasticity [1]
long-term potentiation (LTP) pathway is a significant pathway which is enriched in high-frequency group compared with low-frequency group in undifferentiated Neuro-2a cells
With its ability to endure functional enhancement of synaptic connections, or structural modification of neuronal connectivity, LTP pathway is a critical process for learning and memory [43] and has been relevant in repetitive transcranial magnetic stimulation (rTMS) treatment [4, 8, 36, 37]
Summary
Transcranial magnetic stimulation (TMS) is a non-invasive tool that allows electrical stimulation of the nervous system and could be an ideal treatment tool due to its ability to modify brain plasticity [1]. High-frequency stimulation (>3 Hz) stimulated cortical excitability and generally resulted in an effect that share similar aspects with long-term potentiation (LTP). Low frequency stimulation (≤1 Hz) reduced cortical excitability and induced a reduction in synaptic efficiency which were similar to long-term depression [4, 5]. Various stimulation parameters such as intensity, frequency, overall patterns of stimulation, and periods determine the functional effects of rTMS on cortical excitability [6, 7]. The neural mechanisms related with various stimulation parameters of rTMS remain unclear
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