High-frequency repetitive magnetic stimulation enhances the expression of brain-derived neurotrophic factor through activation of Ca2+-calmodulin-dependent protein kinase II-cAMP-response element-binding protein pathway

Ahreum Baek, Eun Jee Park, Soo Yeon Kim, Bae Geun Nam, Ji Hyun Kim, Sang Woo Jun, Sung Hoon Kim, Sung-Rae Cho

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 CaMKII? 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.

Original languageEnglish
Article number285
JournalFrontiers in Neurology
Volume9
Issue numberMAY
DOIs
Publication statusPublished - 2018 May 7

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Cyclic AMP Response Element-Binding Protein
Brain-Derived Neurotrophic Factor
Transcranial Magnetic Stimulation
Long-Term Potentiation
Genes
Amphetamine-Related Disorders
Encyclopedias
Ionotropic Glutamate Receptors
Calcium-Calmodulin-Dependent Protein Kinases
Nerve Growth Factors
Nervous System Diseases
Transcriptome
Aspartic Acid
Prolactin
Synapses
Cholinergic Agents
Transcriptional Activation
Real-Time Polymerase Chain Reaction
Western Blotting

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

@article{135de4a6ee06459c9cb5f9c7740b02e7,
title = "High-frequency repetitive magnetic stimulation enhances the expression of brain-derived neurotrophic factor through activation of Ca2+-calmodulin-dependent protein kinase II-cAMP-response element-binding protein pathway",
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 CaMKII? 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.",
author = "Ahreum Baek and Park, {Eun Jee} and Kim, {Soo Yeon} and Nam, {Bae Geun} and Kim, {Ji Hyun} and Jun, {Sang Woo} and Kim, {Sung Hoon} and Sung-Rae Cho",
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High-frequency repetitive magnetic stimulation enhances the expression of brain-derived neurotrophic factor through activation of Ca2+-calmodulin-dependent protein kinase II-cAMP-response element-binding protein pathway. / Baek, Ahreum; Park, Eun Jee; Kim, Soo Yeon; Nam, Bae Geun; Kim, Ji Hyun; Jun, Sang Woo; Kim, Sung Hoon; Cho, Sung-Rae.

In: Frontiers in Neurology, Vol. 9, No. MAY, 285, 07.05.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - High-frequency repetitive magnetic stimulation enhances the expression of brain-derived neurotrophic factor through activation of Ca2+-calmodulin-dependent protein kinase II-cAMP-response element-binding protein pathway

AU - Baek, Ahreum

AU - Park, Eun Jee

AU - Kim, Soo Yeon

AU - Nam, Bae Geun

AU - Kim, Ji Hyun

AU - Jun, Sang Woo

AU - Kim, Sung Hoon

AU - Cho, Sung-Rae

PY - 2018/5/7

Y1 - 2018/5/7

N2 - 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 CaMKII? 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.

AB - 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 CaMKII? 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.

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U2 - 10.3389/fneur.2018.00285

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