Abstract
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulatory technique widely used in research, diagnostics, and neuro-psychiatric therapy. Despite its growing popularity, basic molecular mechanisms underlying the clinical effects of rTMS have remained largely under-researched. Here, we present a human-derived neuronal cell culture system responsive to rTMS effects. SH-SY5Y neuroblastoma cells were differentiated by retinoic acid treatment for 10 days, resulting in a neuronal phenotype characterized by upregulation of neuronal marker proteins and generation of an action potential in response to depolarizing current step injection. Repetitive magnetic stimulation of these cells resulted in increased intracellular cAMP levels and increased phosphorylation of transcription factor CREB. Pretreatment with ketamine (1 μM) potentiated, while pretreatment with lithium (2 mM) attenuated this cellular response to repetitive magnetic stimulation. In conclusion, we introduce here a novel in vitro system responding to rTMS at the level of second messenger signaling. The use of human-derived cells with neuron-like properties will prove useful for further studies on the cellular effects of rTMS.
References
Biedler JL, Helson L, Spengler BA (1973) Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res 33:2643–2652
Carlezon WA Jr, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28:436–445
Cohen D, Cuffin BN (1991) Developing a more focal magnetic stimulator. Part I: some basic principles. J Clin Neurophysiol 8:102–111
Gass P, Riva MA (2007) CREB, neurogenesis and depression. Bioessays 29:957–961
Ginty DD, Bonni A, Greenberg ME (1994) Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 77:713–725
Hammonds MD, Shim SS, Feng P, Calabrese JR (2007) Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus. Basic Clin Pharmacol Toxicol 100:356–359
Hellmann J, Rommelspacher H, Muhlbauer E, Wernicke C (2010) Raf kinase inhibitor protein enhances neuronal differentiation in human SH-SY5Y cells. Dev Neurosci 32:33–46
Hellmann J, Rommelspacher H, Wernicke C (2009) Long-term ethanol exposure impairs neuronal differentiation of human neuroblastoma cells involving neurotrophin-mediated intracellular signaling and in particular protein kinase C. Alcohol Clin Exp Res 33:538–550
Ji RR, Schlaepfer TE, Aizenman CD, Epstein CM, Qiu D, Huang JC, Rupp F (1998) Repetitive transcranial magnetic stimulation activates specific regions in rat brain. Proc Natl Acad Sci USA 95:15635–15640
Kranaster L, Kammerer-Ciernioch J, Hoyer C, Sartorius A (2011) Clinically favourable effects of ketamine as an anaesthetic for electroconvulsive therapy: a retrospective study. Eur Arch Psych Clin Neurosci
Kronenberg G, Kirste I, Inta D, Chourbaji S, Heuser I, Endres M, Gass P (2009) Reduced hippocampal neurogenesis in the GR(±) genetic mouse model of depression. Eur Arch Psych Clin Neurosci 259:499–504
Lee JS, Jang DJ, Lee N, Ko HG, Kim H, Kim YS, Kim B, Son J, Kim SH, Chung H, Lee MY, Kim WR, Sun W, Zhuo M, Abel T, Kaang BK, Son H (2009) Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors. J Neurosci 29:8493–8505
Muller D, Djebbara-Hannas Z, Jourdain P, Vutskits L, Durbec P, Rougon G, Kiss JZ (2000) Brain-derived neurotrophic factor restores long-term potentiation in polysialic acid-neural cell adhesion molecule-deficient hippocampus. Proc Natl Acad Sci USA 97:4315–4320
Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16:2365–2372
Platz T, Rothwell JC (2010) Brain stimulation and brain repair-rTMS: from animal experiment to clinical trials—what do we know? Restor Neurol Neurosci 28:387–398
Reus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, Souza CT, Quevedo J (2011) Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res 221:166–171
Ridding MC, Rothwell JC (2007) Is there a future for therapeutic use of transcranial magnetic stimulation? Nat Rev Neurosci 8:559–567
Shaul U, Ben-Shachar D, Karry R, Klein E (2003) Modulation of frequency and duration of repetitive magnetic stimulation affects catecholamine levels and tyrosine hydroxylase activity in human neuroblastoma cells: implication for the antidepressant effect of rTMS. Int J Neuropsychopharmacol 6:233–241
Sontag W, Kalka D (2006) No effect of pulsed electromagnetic fields on PC12 and HL-60 cells. Radiat Environ Biophys 45:63–71
Sontag W, Kalka D (2007) Repetitive transcranial magnetic stimulation does not influence immunological HL-60 cells and neuronal PC12 cells. Int J Radiat Biol 83:603–615
Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS (2000) cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20:4030–4036
Unsoeld T, Stradomska AM, Wang R, Rathjen FG, Juttner R (2008) Early maturation of GABAergic synapses in mouse retinal ganglion cells. Int J Dev Neurosci 26:233–238
Vollmayr B, Mahlstedt MM, Henn FA (2007) Neurogenesis and depression: what animal models tell us about the link. Eur Arch Psych Clin Neurosci 257:300–303
Acknowledgments
This study was supported by grants from the VolkswagenFoundation (Lichtenberg program), Bundesministerium für Bildung und Forschung (Center for Stroke Research Berlin), Deutsche Forschungsgemeinschaft (DFG RA 424/5-1 to R.J.) and the Hermann and Lilly Schilling Foundation.
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Hellmann, J., Jüttner, R., Roth, C. et al. Repetitive magnetic stimulation of human-derived neuron-like cells activates cAMP-CREB pathway. Eur Arch Psychiatry Clin Neurosci 262, 87–91 (2012). https://doi.org/10.1007/s00406-011-0217-3
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DOI: https://doi.org/10.1007/s00406-011-0217-3