NM  Vol.4 No.4 , December 2013
Kinetics of Norepinephrine- and Serotonin-Induced BDNF Release in Cultured Embryonic Hippocampal Neurons
ABSTRACT


The primary neurotransmitters targeted by currently used antidepressants, such as duloxetine, venlafaxine and fluoxetine, are serotonin and norepinephrine, which also are released in significant amounts in the central nervous system in response to sympathetic nervous system activation. In cultured hippocampal neurons, we have previously shown that norepinephrine induces increased expression of brain-derived neurotrophic factor (BDNF), the PI-3 K/Akt, MAPK pro-survival pathways, the BDNF receptor, TrkB, a transcription factor, and cyclic AMP response element binding protein (CREB). In the present study, we extend these findings of increased BDNF expression to its kinetics of release into the surrounding media. We also evaluate these two cell survival pathways, TrkB and CREB, in response to application of serotonin and/or norepinephrine. Serotonin elicits an earlier, but brief expression and release of BDNF, whereas norepinephrine elicits a more delayed and sustained release of BDNF. In response to both norepinephrine and 5-HT, the presence of BDNF in lysates and subsequent release into the media is significantly increased out to 4 h, as is PI-3 K/Akt activation. Together, these two neurotransmitters increase BDNF expression and release covering the entire 8 h continuum evaluated. The results of this study provide further evidence for a G protein-coupled receptor and a crosstalk-to-TrkB receptor with transactivation signaling across pathways.



Cite this paper
M. Chen and A. Russo-Neustadt, "Kinetics of Norepinephrine- and Serotonin-Induced BDNF Release in Cultured Embryonic Hippocampal Neurons," Neuroscience and Medicine, Vol. 4 No. 4, 2013, pp. 194-207. doi: 10.4236/nm.2013.44031.
References
[1]   A. Gärtner and V. Staiger, “Neurotrophin Secretion from Hippocampal NeuronsEvoked by Long-Term-Potentiation-Inducing Electrical Stimulation Patterns,” Proceedings of the National Academy of Sciences USA, Vol. 99, No. 9, 2002, pp. 6386-6391.
http://dx.doi.org/10.1073/pnas.092129699

[2]   M. E. Hopkins, R. Nitecki and D. J. Bucci, “Physical Exercise during Adolescence versus Adulthood: Differential Effects on Object Recognition Memory and BDNF Levels,” Neuroscience, Vol. 194, 2011, pp. 84-94.
http://dx.doi.org/10.1016/j.neuroscience.2011.07.071

[3]   T. Kobilo, Q-R. Liu, K. Gandhi, M. Mughal, Y. Shaham and H. van Praag, “Running Is the Neurogenic and Neurotrophic Stimulus in Environmental Enrichment,” Learning & Memory, Vol. 18, No. 9, 2011, pp. 605-609.
http://dx.doi.org/10.1101/lm.2283011

[4]   G. Baj, V. D’Alessandro, L. Musazzi, A. Mallei, C. R. Sartori, M. Sciancalepore, D. Tardito, F. Langone, M. Popoli and E. Tongiorgi, “Physical Exercise and Antidepressants Enhance BDNF Targeting in hippocampal CA3 Dendrites: Further Evidence of a Spatial Code for BDNF Splice Variants,” Neuropsychopharmacology, Vol. 37, No. 7, 2012, pp. 1600-1611.
http://dx.doi.org/10.1038/npp.2012.5

[5]   Y. Yagasaki, T. Numakawa, E. Kumamaru, T. Hayashi, T.-P. Su and H. Kunugi, “Chronic Antidepressants Potentiate via Sigma-1 Receptors the Brain-Derived Neurotrophic Factor-Induced Signaling for Glutamate Release,” Journal of Biological Chemistry, Vol. 281, No. 18, 2006, pp. 12941-12949.
http://dx.doi.org/10.1074/jbc.M508157200

[6]   P. Rasmussen, P. Brassard, H. Adser, M. V. Pedersen, L. Leick, E. Hart, N. H. Secher, B. K. Pedersen and H. Pilegaard, “Evidence for a Release of Brain-Derived Neurotrophic Factor from the Brain During Exercise,” Experimental Physiology, Vol. 94, No. 10, 2009, pp. 1062-1069.
http://dx.doi.org/10.1113/expphysiol.2009.048512

[7]   A. A. Russo-Neustadt and M. J. Chen, “Brain-Derived Neurotrophic Factor and Antidepressant Activity,” Current Pharmaceutical Design, Vol. 11, No. 12, 2005, pp. 1495-1510. http://dx.doi.org/10.2174/1381612053764788

[8]   M. J. Chen, A. A. Russo-Neustadt, “Running Exercise-Induced Up-Regulation of Hippocampal Brain-Derived Neurotrophic Factor is CREB-Dependent,” Hippocampus, Vol. 19, No. 10, 2009, pp. 962-972.
http://dx.doi.org/10.1002/hipo.20579

[9]   M. C. Lee, M. Okamoto, Y. F. Liu, K. Inoue, T. Matsui, H. Nogami and H. Soya, “Voluntary Resistance Running with Short Distance Enhances Spatial Memory Related to Hippocampal BDNF Signaling,” Journal of Applied Physiology, Vol. 113, No. 8, 2012, pp. 1260-1266.
http://dx.doi.org/10.1152/japplphysiol.00869.2012

[10]   A. Balkowiec and D. M. Katz, “Cellular Mechanisms Regulating Activity-Dependent Release of Native BrainDerived Neurotrophic Factor from Hippocampal Neurons,” Journal of Neuroscience, Vol. 22, No. 23, 2002, pp. 10399-10407.

[11]   F. Zafra, D. Lindholm, E. Castrén, J. Hartikka, and H. Thoenen, “Regulation of Brain-Derived Neurotrophic Factor and Nerve Growth Factor mRNA in Primary Cultures of Hippocampal Neurons and Astrocytes,” Journal of Neuroscience, Vol. 12, No. 12, 1992, pp. 4793-4799.

[12]   A. Androutsellis-Theotokis, W. J. McCormack, H. F. Bradford, G. M. Stern and F. B. Pliego-Rivero, “The Depolarisation-Induced Release of [125I]BDNF from Brain Tissue,” Brain Research, Vol. 743, No. 1-2, 1996, pp. 40-48. http://dx.doi.org/10.1016/S0006-8993(96)00981-X

[13]   M. Hartmann, R. Heumann and V. Lessmann, “Synaptic Secretion of BDNF after High-Frequency Stimulation of Glutamatergic Synapses,” EMBO Journal, Vol. 20, No. 21, 2001, pp. 5887-5897.
http://dx.doi.org/10.1093/emboj/20.21.5887

[14]   M. Kojima, N. Takei, T. Numakawa, Y. Ishikawa, S. Suzuki, T. Matsumoto, R. Katoh-Semba, H. Nawa and H. Hatanaka, “Biological Characterization and Optical Imaging of Brain-Derived Neurotrophic Factor-Green Fluorescent Protein Suggest an Activity-Dependent Local Release of Brain-Derived Neurotrophic Factor in Neurites of Cultured Hippocampal Neurons,” Journal of Neuroscience Research, Vol. 64, No. 1, 2001, pp. 1-10.
http://dx.doi.org/10.1002/jnr.1080

[15]   J. Goggi, I. A. Pullar, S. L. Carney and H. F. Bradford, “The Control of [125I]BDNF Release from Striatal Rat Brain Slices,” Brain Research, Vol. 967, No. 1-2, 2003, pp. 201-209.
http://dx.doi.org/10.1016/S0006-8993(03)02225-X

[16]   S. Santi, S. Cappello, M. Riccio, M. Bergami, G. Aicardi, U. Schenk, M. Matteoli and M. Canossa, “Hippocampal Neurons Recycle BDNF for Activity-Dependent Secretion and LTP Maintenance,” The EMBO Journal, Vol. 25, No. 18, 2006, pp. 4372-4380.
http://dx.doi.org/10.1038/sj.emboj.7601303

[17]   J. Yang, C.-J. Siao, G. Nagappan, T. Marinic, D. Jing, K. McGrath, Z.-Y. Chen, W. Mark, L. Tessarollo, F. S. Lee, B. Lu and B. L. Hempstead, “Neuronal Release of Pro-BDNF,” Nature Neuroscience, Vol. 12, No. 2, 2009, pp. 113-115. http://dx.doi.org/10.1038/nn.2244

[18]   A. M. Marini, S. J. Rabin, R. H. Lipsky and I. Mocchetti, (1998) “Activity-Dependent Release of Brain-Derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-D-Aspartate,” Journal of Biological Chemistry, Vol. 273, No. 45, 1998, pp. 29394-29399.
http://dx.doi.org/10.1074/jbc.273.45.29394

[19]   R. H. Lipsky, K. Xu, D. Zhu, C. Kelly, A. Terhakopian, A. Novelli and A. M. Marini, “Nuclear Factor Kappa B is a Critical Determinant in N-Methyl-D-Aspartate Receptor-Mediated Neuroprotection,” Journal of Neurochemistry, Vol. 78, No. 2, 2001, pp. 254-264.
http://dx.doi.org/10.1046/j.1471-4159.2001.00386.x

[20]   X. Wu, D. Zhu, X. Jiang, P. Okagaki, K. Mearow, G. Zhu, S. McCall, K. Banaudha, R. H. Lipsky and A. M. Marini, “AMPA Protects Cultured Neurons against Glutamate Excitotoxicity through a Phosphatidylinositol 3-Kinase-Dependent Activation in Extracellular Signal-Regulated Kinase to Upregulate BDNF Gene Expression,” Journal of Neurochemistry, Vol. 90, No. 4, 2004, pp. 807-818.
http://dx.doi.org/10.1111/j.1471-4159.2004.02526.x

[21]   X. Jiang, F. Tian, K. Mearow, P. Okagaki, R. H. Lipsky and A. M. Marini, “The Excitoprotective Effect of N-Methyl-D-Aspartate Receptors is Mediated by a Brain-Derived Neurotrophic Factor Autocrine Loop in Cultured Hippocampal Neurons,” Journal of Neurochemistry, Vol. 94, No. 3, 2005, pp. 713-722.
http://dx.doi.org/10.1111/j.1471-4159.2005.03200.x

[22]   R. Kolarow, T. Brigadski and V. Lessmann, “Postsynaptic Secretion of BDNF and NT-3 from Hippocampal Neurons Depends on Calcium-Calmodulin Kinase II Signaling and Proceeds via Delayed Fusion Pore Opening,” Journal of Neuroscience, Vol. 27, No. 39, 2007, pp. 10350-10364.
http://dx.doi.org/10.1523/JNEUROSCI.0692-07.2007

[23]   E. C. Gunther, C. S. Von Bartheld, L. J. Goodman, J. E. Johnson and M. Bothwell, “The G-Protein Inhibitor, Pertussis Toxin, Inhibits the Secretion of Brain-Derived Neurotrophic Factor,” Neuroscience, Vol. 100, No. 3, 2000, pp. 569-579.
http://dx.doi.org/10.1016/S0306-4522(00)00309-2

[24]   M. J. Chen, T. V. Nguyen, C. J. Pike and A. A. RussoNeustadt, “Norepinephrine Induces BDNF and Activates the PI-3K and MAPK Cascades in Embryonic Hippocampal Neurons,” Cellular Signaling, Vol. 19, No. 1, 2007, pp. 114-128.
http://dx.doi.org/10.1016/j.cellsig.2006.05.028

[25]   N. J. Patel, M. J. Chen and A. A. Russo-Neustadt, “Norpinephrine and Nitric Oxide Promote Cell Survival Signaling in Hippocampal Neurons,” European Journal of Pharmacology, Vol. 633, No. 1-3, 2010, pp. 1-9.
http://dx.doi.org/10.1016/j.ejphar.2010.01.012

[26]   D. Yang, M. Chen and A. Russo-Neustadt, “Antidepressants are Neuroprotective Against Nutrient Deprivation Stress in Hippocampal Neurons,” European Journal of Neuroscience, Vol. 36, No. 5, 2012, pp. 2573-2587.
http://dx.doi.org/10.1111/j.1460-9568.2012.08187.x

[27]   R. K. Dishman, K. J. Renner, J. E. Whitte-Welkley, K. A. Burke, B. N. Bunnell, “Treadmill Exercise Training Augments Brain Norepinephrine Response to Familiar and Novel Stress,” Brain Research Bulletin, Vol. 52, No. 5, 2000, pp. 337-342.
http://dx.doi.org/10.1016/S0361-9230(00)00271-9

[28]   J. F. Cryan, O. F. O’Leary, S. H. Jin, J. C. Friedland, M. Ouyang, B. R. Hirsch, M. E. Page, A. Dalvi,S. A. Thomas and I. Lucki, “Norepinephrine-Deficient Mice Lack Responses to Antidepressant Drugs, Including Selective Serotonin Reuptake Inhibitors,” Proceedings of the National Academy of Sciences USA, Vol. 101, No. 21, 2004, pp. 8186-8191. http://dx.doi.org/10.1073/pnas.0401080101

[29]   D. J. Nutt, “The Neuropharmacology of Serotonin and Norepinephrine in Depression,” International Clinical Psychopharmacology, Vol. 17, Suppl. 1, 2002, pp. S1-S12.
http://dx.doi.org/10.1097/00004850-200206001-00002

[30]   J. E. Malberg and J. A. Blendy, “Antidepressant Action: To the Nucleus and Beyond,” Trends in Pharmacological Sciences, Vol. 26, No. 12, 2005, pp. 631-638.
http://dx.doi.org/10.1016/j.tips.2005.10.005

[31]   G. A. Banker and W. M. Cowan, “Rat Hippocampal Neurons in Dispersed Cell Culture,” Brain Research, Vol. 126, No. 3, 1977, pp. 397-442.
http://dx.doi.org/10.1016/0006-8993(77)90594-7

[32]   D. S. Cowan, N. N. Farley-Johnson and T. Travkina, “5-HT1A Receptors Couple to Activation of Akt, but not Extracellular-Regulated Kinase (ERK) in Cultured Hippocampal Neurons,” Journal of Neurochemistry, Vol. 93, No. 4, 2005, pp. 910-917.
http://dx.doi.org/10.1111/j.1471-4159.2005.03107.x

[33]   U. K. Laemmli, “Cleavage of Structural Proteins During the Assembly of the Head of Bacteriophage T4,” Nature, Vol. 227, No. 5259, 1970, pp. 680-685.
http://dx.doi.org/10.1038/227680a0

[34]   A. Barnea, J. Roberts and S. D. Croll, “Continuous Exposure to Brain-Derived Neurotrophic Factor is Required for Persistent Activation of TrkB Receptor, the ERK Signaling Pathway, and the Induction of Neuropeptide Y Production in Cortical Cultures,” Brain Research, Vol. 1020, Vol. 1-2, 2004, pp. 106-117.

[35]   D. Lindholm, P. Carroll, G. Tzimagiorgis and H. Thoenen, “Autocrine-Paracrine Regulation of Hippocampal Neuron Survival by IGF-1 and the Neurotrophins BDNF, NT-3 and NT-4,” European Journal of Neuroscience, Vol. 8, No. 7, 1996, pp. 1452-1460.
http://dx.doi.org/10.1111/j.1460-9568.1996.tb01607.x

[36]   W. J. Tyler and L. D. Pozzo-Miller, “BDNF Enhances Quantal Neurotransmitter Release and Increases the Number of Docked Vesicles at the Active Zones of Hippocampal Excitatory Synapses,” Journal of Neuroscience, Vol. 21, No. 12, 2001, pp. 4249-4258.

[37]   W. J. Tyler, S. P. Perrett and L. D. Pozzo-Miller, “The Role of Neurotrophins in Neurotransmitter Release,” The Neuroscientist, Vol. 8, No. 6, 2002, pp. 524-531.
http://dx.doi.org/10.1177/1073858402238511

[38]   W. J. Tyler, X.-L. Zhang, K. Hartman, J. Winterer, W. Muller, P. K. Stanton and L. Pozzo-Miller, “BDNF Increases Release Probability and the Size of a Rapidly Recycling Vesicle Pool within Rat Hippocampal Excitatory Synapses,” Journal of Physiology, Vol. 574, No. 3, 2006, pp. 787-803.
http://dx.doi.org/10.1113/jphysiol.2006.111310

[39]   I. Alleman, H. Fiumelli, P. J. Magistretti and J.-L. Martin, “Fluoxetine Regulates the Expression of Neurotrophic/Growth Factors and Glucose Metabolism in Astrocytes,” Psychopharmacology, Vol. 216, No. 1, 2011, pp. 75-84. http://dx.doi.org/10.1007/s00213-011-2190-y

[40]   P. R. Tsuruda, J. Yung, W. J. Martin, R. Chang, N. Mai and J. A. M. Smith, “Influence of Ligand Binding Kinetics on Functional Inhibition of Human Recombinant Serotonin and Norepinephrine Transporters,” Journal of Pharmacological and Toxicological Methods, Vol. 61, No. 2, 2010, pp. 192-204.
http://dx.doi.org/10.1016/j.vascn.2009.12.003

[41]   D. Zhu, R. H. Lipsky and A. M. Marini, “Co-Activation of the Phosphatidylinositol-3-Kinase/Akt Signaling Pathway by N-Methyl-D-Aspartate and TrkB Receptors in Cerebellar Granule Cell Neurons,” Amino Acids, Vol. 23, No. 1-3, 2002, pp. 11-17.
http://dx.doi.org/10.1007/s00726-001-0103-9

[42]   H. Yano and M. V. Chao, “Neurotrophin Receptor Structure and Interactions,” Pharmaceutica Acta Helvetiae, Vol. 74, No. 2-3, 2000, pp. 253-260.
http://dx.doi.org/10.1016/S0031-6865(99)00036-9

[43]   Q. Ma, “Beneficial Effects of Moderate Voluntary Physical Exercise and Its Biological Mechanisms on Brain Health,” Neuroscience Bulletin, Vol. 24, No. 4, 2008, pp. 265-270. http://dx.doi.org/10.1007/s12264-008-0402-1

[44]   V. Lessmann, K. Gottmann and M. Malcangio, “Neurotrophin Secretion: Current Facts and Future Prospects,” Progress in Neurobiology, Vol. 69, No. 5, 2003, pp. 341-374. http://dx.doi.org/10.1016/S0301-0082(03)00019-4

[45]   C.-P. Shen, Y. Tsimberg, C. Salvadore and E. Meller, “Activation of Erk and JNK MAPK Pathways by Acute Swim Stress in Rat Brain Regions,” BMC Neuroscience, Vol. 5, 2004, pp. 36.
http://dx.doi.org/10.1186/1471-2202-5-36

[46]   G. Aicardi, E. Argilli, S. Cappello, S. Santi, M. Riccio, H. Thoenen and M. Canossa, “Induction of Long-Term Potentiation and Depression is Reflected by Corresponding Changes in Secretion of Endogenous Brain-Derived Neurotrophic Factor,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 44, 2004, pp. 15788-15792.
http://dx.doi.org/10.1073/pnas.0406960101

[47]   V. Lessmann and T. Brigadski, “Mechanisms, Locations, and Kinetics of Synaptic BDNF Secretion: An Update,” Neuroscience Research, Vol. 65, No. 1, 2009, pp. 11-22.
http://dx.doi.org/10.1016/j.neures.2009.06.004

[48]   I. Buldyrev, N. M. Tanner, H.-Y. Hsieh, E. G. Dodd, L. T. Nguyen and A. Balkowiec, “Calcitonin Gene-Related Peptide Enhances Release of Native Brain-Derived Neurotrophic Factor from Trigeminal Ganglion Neurons,” Journal of Neurochemistry, Vol. 99, No. 5, 2006, pp. 1338-1350.
http://dx.doi.org/10.1111/j.1471-4159.2006.04161.x

[49]   T. Brigadski, M. Hartmann and V. Lessmann, “Differential Vesicular Targeting and Time Course of Synaptic Secretion of the Mammalian Neurotrophins,” Journal of Neuroscience, Vol. 25, No. 33, 2005, pp. 7601-7614.
http://dx.doi.org/10.1523/JNEUROSCI.1776-05.2005

[50]   M. Bergami, S. Santi, E. Formaggio, C. Cagnoli, C. Verderio, R. Blum, B. Berninger, M. Matteoli and M. Canossa, “Uptake and Recycling of Pro-BDNF for Transmitter-Induced Secretion by Cortical Astrocytes,” Journal of Cell Biology, Vol. 183, No. 2, 2008, pp. 213-221.
http://dx.doi.org/10.1083/jcb.200806137


 
 
Top