Abstract
Tricyclic antidepressants and selective serotonin reuptake inhibitors are considered in theory to induce the outflow of neurotransmitters, norepinephrine, and serotonin from the synapses as a consequence of inhibiting their reuptake into the nerve terminals, resulting in the stimulation of glial cells surrounding the synapses in the brain. Then, we have investigated the direct actions of neurotransmitters on glial cell metabolism and function using rat C6 glioma cells as an in vitro model system and suggested that these neurotransmitters induce their differentiation probably through the production of 5α-reduced neurosteroids. On the other hand, the stimulation of the glioma cells with serotonin has been reported to enhance brain-derived neurotrophic factor (BDNF) gene expression, which may be closely related to the beneficial effects of antidepressant drugs. In the present study, to evaluate BDNF expression in differentiated glial cells, the glioma cells were pretreated with progesterone, and the effect of serotonin on BDNF messenger RNA levels in these cells was examined. Progesterone pretreatment enhanced the stimulatory action of serotonin on BDNF gene expression, and the enhancement of serotonin action observed in the cells pretreated with progesterone was almost completely abolished by finasteride, an inhibitor of the enzyme involved in the production of 5α-reduced neurosteroids. These findings propose the possibility that neurosteroid-mediated glial cell differentiation may result in the enhancement of serotonin-stimulated BDNF gene expression, which is considered to contribute to the survival, regeneration, and plasticity of neuronal cells in the brain, and hence, leading to the improvement of mood disorders and other symptoms in depressive patients.
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Bova, R., Micheli, M. R., Qualadrucci, P., & Zucconi, G. G. (1998). BDNF and trkB mRNAs oscillate in rat brain during the light-dark cycle. Molecular Brain Research, 57, 321–324.
Bramham, C. R., & Messaoudi, E. (2005). BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis. Progress in Neurobiology, 76, 99–125.
Chomczynski, P., & Sacchi, N. (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Analytical Biochemistry, 162, 156–159.
Duman, R. S., Malberg, J., Nakagawa, S., & D'Sa, C. (2000). Neuronal plasticity and survival in mood disorders. Biological Psychiatry, 48, 732–739.
Govindarajan, A., Rao, B. S., Nair, D., Trinh, M., Mawjee, N., Tonegawa, S., et al. (2006). Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proceedings of the National Academy of Sciences of the United States of America, 103, 13208–13213.
Haydon, P. G. (2001). GLIA: Listening and talking to the synapse. Nature Reviews. Neuroscience, 2, 185–193.
Hoshaw, B. A., Malberg, J. E., & Lucki, I. (2005). Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Research, 1037, 204–208.
Kuipers, S. D., & Bramham, C. R. (2006). Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: New insights and implications for therapy. Current Opinion in Drug Discovery & Development, 9, 580–586.
Melcangi, R. C., Riva, M. A., Fumagalli, F., Magnaghi, V., Racagni, G., & Martini, L. (1996). Effect of progesterone, testosterone and their 5α-reduced metabolites on GFAP gene expression in type 1 astrocytes. Brain Research, 711, 10–15.
Meller, R., Babity, J. M., & Grahame-Smith, D. G. (2002). 5-HT2A receptor activation leads to increased BDNF mRNA expression in C6 glioma cells. Neuromolecular Med, 1, 197–205.
Molteni, R., Calabrese, F., Bedogni, F., Tongiorgi, E., Fumagalli, F., Racagni, G., et al. (2006). Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions. International Journal of Neuropsychopharmacology, 9, 307–317.
Morita, K., Arimochi, H., & Her, S. (2005). Serotonergic 5-HT2A receptor stimulation induces steroid 5α-reductase gene expression in rat C6 glioma cells via transcription factor Egr-1. Molecular Brain Research, 139, 193–200.
Morita, K., Arimochi, H., Itoh, H., & Her, S. (2006). Possible involvement of 5α-reduced neurosteroids in adrenergic and serotonergic stimulation of GFAP gene expression in rat C6 glioma cells. Brain Research, 1085, 49–56.
Morita, K., Arimochi, H., & Tsuruo, Y. (2004). Adrenergic activation of steroid 5α-reductase gene expression in rat C6 glioma cells: Involvement of cyclic AMP/protein kinase A-mediated signaling pathway. Journal of Molecular Neuroscience, 22, 205–212.
Morita, K., Tsuruo, Y., Ishimura, K., Her, S., Bell, R. A., & Wong, D. L. (1999). Influence of serum-free culture conditions on steroid 5α-reductase mRNA expression in rat C6 glioma cells. Brain Research, 830, 179–182.
Nibuya, M., Morinobu, S., & Duman, R. S. (1995). Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. Journal of Neuroscience, 15, 7539–7547.
Nibuya, M., Nestler, E. J., & Duman, R. S. (1996). Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. Journal of Neuroscience, 16, 2365–2372.
Ren-Patterson, R. F., Cochran, L. W., Holmes, A., Sherrill, S., Huang, S. J., Tolliver, T., et al. (2005). Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. Journal of Neuroscience Research, 79, 756–771.
Russo-Neustadt, A., Beard, R. C., & Cotman, C. W. (1999). Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology, 21, 679–682.
Russo-Neustadt, A. A., Beard, R. C., Huang, Y. M., & Cotman, C. W. (2000). Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience, 101, 305–312.
Russo-Neustadt, A., Ha, T., Ramirez, R., & Kesslak, J. P. (2001). Physical activity-antidepressant treatment combination: Impact on brain-derived neurotrophic factor and behavior in an animal model. Behavioural Brain Research, 120, 87–95.
Segovia, J., Lawless, G. M., Tillakaratne, N. J., Brenner, M., & Tobin, A. J. (1994). Cyclic AMP decreases the expression of a neuronal marker (GAD67) and increases the expression of an astroglia marker (GFAP) in C6 cells. Journal of Neurochemistry, 63, 1218–1225.
Shirayama, Y., Chen, A. C., Nakagawa, S., Russell, D. S., & Duman, R. S. (2002). Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. Journal of Neuroscience, 22, 3251–3261.
Slezak, M., & Pfrieger, F. W. (2003). New roles for astrocytes: Regulation of CNS synaptogenesis. Trends in Neurosciences, 26, 531–535.
Slezak, M., Pfrieger, F. W., & Soltys, Z. (2006). Synaptic plasticity, astrocytes and morphological homeostasis. Journal of Physiology (Paris), 99, 84–91.
Tournell, C. E., Bergstrom, R. A., & Ferreira, A. (2006). Progesterone-induced agrin expression in astrocytes modulates glia-neuron interactions leading to synapse formation. Neuroscience, 141, 1327–1338.
Vinet, J., Carra, S., Blom, J. M., Brunello, N., Barden, N., & Tascedda, F. (2004). Chronic treatment with desipramine and fluoxetine modulate BDNF, CaMKKalpha and CaMKKbeta mRNA levels in the hippocampus of transgenic mice expressing antisense RNA against the glucocorticoid receptor. Neuropharmacology, 47, 1062–1069.
Vogel, G. (2000). New brain cells prompt new theory of depression. Science, 290, 258–259.
Zetterstrom, T. S., Pei, Q., Madhav, T. R., Coppell, A. L., Lewis, L., & Grahame-Smith, D. G. (1999). Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain. Neuropharmacology, 38, 1063–1073.
Acknowledgment
This work was supported in part by the research grants from AstraZeneca Plc. (London) and the research aid of Daiwa Securities Health Foundation (Japan).
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Morita, K., Her, S. Progesterone Pretreatment Enhances Serotonin-Stimulated BDNF Gene Expression in Rat C6 Glioma Cells Through Production of 5α-Reduced Neurosteroids. J Mol Neurosci 34, 193–200 (2008). https://doi.org/10.1007/s12031-007-9034-6
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DOI: https://doi.org/10.1007/s12031-007-9034-6