NM  Vol.5 No.4 , September 2014
The Biological Actions and Mechanisms of Brain-Derived Neurotrophic Factor in Healthy and Disordered Brains
Abstract: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that elicits neuronal survival and differentiation, synaptic transmission, and the modulation of synaptic plasticity. The biological actions of BDNF are mediated via two distinct receptors: the high-affinity tropomyosin-related kinase B (TrkB) receptor and the low-affinity p75 neurotrophin receptor (p75NTR). Recent findings regarding the actions and mechanisms of BDNF are reviewed here. Activity-dependent synaptic plasticity, as exemplified by long-term potentiation (LTP) and long-term depression (LTD), underlies the cellular mechanism of learning and memory. An accumulating body of evidence shows that BDNF modulates synaptic plasticity. This function requires extracellular neurotrophin release, synaptic activity-dependent local protein synthesis. In addition, a precursor of BDNF, proBDNF, is emerging as a new ligand with biological activities that are distinct from those of BDNF. The proteolytic cleavage of proBDNF is also proposed as a mechanism that determines the direction of BDNF actions. This review discusses the post-translational processing of proBDNF, the modulatory roles of the human BDNF polymorphism Val66Met, recent reports of the novel mechanisms of BDNF expression, and clinical reports showing the roles of BDNF in the blood. Taken together, these data provide new insights into the biological roles of BDNF and its related molecules in the central nervous system.
Cite this paper: Mizui, T. , Tanima, Y. , Komatsu, H. , Kumanogoh, H. and Kojima, M. (2014) The Biological Actions and Mechanisms of Brain-Derived Neurotrophic Factor in Healthy and Disordered Brains. Neuroscience and Medicine, 5, 183-195. doi: 10.4236/nm.2014.54021.

[1]   Levi-Montalcini, R. and Hamburge, V. (1953) A Diffusible Agent of Mouse Sarcoma, Producing Hyperplasia of Sympathetic-Ganglia and Hyperneurotization of Viscera in the Chick Embryo. Journal of Experimental Zoology, 123, 233-287.

[2]   Cohen, S. and Levi-Montalcini, R. (1956) A Nerve Growth-Stimulating Factor Isolated from Snake Venom. Proceedings of the National Academy of Sciences of the United States of America, 42, 571-574.

[3]   Cohen, S. (1960) Purification of a Nerve-Growth Promoting Protein from the Mouse Salivery Gland and Its Neuro-Cytotoxic Antiserum. Proceedings of the National Academy of Sciences of the United States of America, 46, 302-311.

[4]   Bocchini, V. and Angeletti, P.U. (1969) The Nerve Growth Factor: Purification as a 30,000-Molecular-Weight Protein. Proceedings of the National Academy of Sciences of the United States of America, 64, 787-794.

[5]   Barde, Y.A., Edgar, D. and Thoenen, H. (1982) Purification of a New Neurotrophic Factor from Mammalian Brain. The EMBO Journal, 1, 549-553.

[6]   Leibrock, J., Lottspeich, F., Hohn, A., Hofer, M., Hengerer, B., Masiakowski, P., Thoenen, H. and Barde, Y.A. (1989) Molecular Cloning and Expression of Brain-Derived Neurotrophic Factor. Nature, 341, 149-152.

[7]   Bibel, M. and Barde, Y.A. (2000) Neurotrophins: Key Regulators of Cell Fate and Cell Shape in the Vertebrate Nervous System. Genes & Development, 14, 2919-2937.

[8]   Chao, M.V. (2003) Neurotrophins and Their Receptors: A Convergence Point for Many Signalling Pathways. Nature Reviews Neuroscience, 4, 299-309.

[9]   Reichardt, L.F. (2006) Neurotrophin-Regulated Signalling Pathways. Philosophical Transactions of the Royal Society B: Biological Sciences, 361, 1545-1564.

[10]   Lu, B., Pang, P.T. and Woo, N.H. (2005) The Yin and Yang of Neurotrophin Action. Nature Reviews Neuroscience, 6, 603-614.

[11]   Kolbeck, R., Jungbluth, S. and Barde, Y.A. (1994) Characterisation of Neurotrophin Dimers and Monomers. European Journal of Biochemistry, 225, 995-1003.

[12]   Egan, M.F., Kojima, M., Callicott, J.H., Goldberg, T.E., Kolachana, B.S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D., Dean, M., Lu, B. and Weinberger, D.R. (2003) The BDNF Val66Met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function. Cell, 112, 257-269.

[13]   Bath, K.G. and Lee, F.S. (2006) Variant BDNF (Val66Met) Impact on Brain Structure and Function. Cognitive, Affective, & Behavioral Neuroscience, 6, 79-85.

[14]   Liepinsh, E., Ilag, L.L., Otting, G. and Ibáñez, C.F. (1997) NMR Structure of the Death Domain of the p75 Neurotrophin Receptor. The EMBO Journal, 16, 4999-5005.

[15]   He, X.L. and Garcia, K.C. (2004) Structure of Nerve Growth Factor Complexed with the Shared Neurotrophin Receptor p75. Science, 304, 870-875.

[16]   Hempstead, B.L. (2002) The Many Faces of p75NTR. Current Opinion in Neurobiology, 12, 260-267.

[17]   Lee, R., Kermani, P., Teng, K.K. and Hempstead, B.L. (2001) Regulation of Cell Survival by Secreted Proneurotrophins. Science, 294, 1945-1948.

[18]   Teng, H.K., Teng, K.K., Lee, R., Wright, S., Tevar, S., Almeida, R.D., Kermani, P., Torkin, R., Chen, Z.Y., Lee, F.S., Kraemer, R.T., Nykjaer, A. and Hempstead, B.L. (2005) ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin. The Journal of Neuroscience, 25, 5455-5463.

[19]   Koshimizu, H., Kiyosue, K., Hara, T., Hazama, S., Suzuki, S., Uegaki, K., Nagappan, G., Zaitsev, E., Hirokawa, T., Tatsu, Y., Ogura, A., Lu, B. and Kojima, M. (2009) Multiple Functions of Precursor BDNF to CNS Neurons: Negative Regulation of Neurite Growth, Spine Formation and Cell Survival. Molecular Brain, 2, 27.

[20]   Taylor, A.R., Gifondorwa, D.J., Robinson, M.B., Strupe, J.L., Prevette, D., Johnson, J.E., Hempstead, B., Oppenheim, R.W. and Milligan, C.E. (2012) Motoneuron Programmed Cell Death in Response to ProBDNF. Developmental Neurobiology, 72, 699-712.

[21]   Nykjaer, A., Lee, R., Teng, K.K., Jansen, P., Madsen, P., Nielsen, M.S., Jacobsen, C., Kliemannel, M., Schwarz, E., Willnow, T.E., Hempstead, B.L. and Petersen, C.M. (2004) Sortilin Is Essential for ProNGF-Induced Neuronal Cell Death. Nature, 427, 843-848.

[22]   Khatib, A.M., Siegfried, G., Chrétien, M., Metrakos, P. and Seidah, N.G. (2002) Proprotein Convertases in Tumor Progression and Malignancy: Novel Targets in Cancer Therapy. The American Journal of Pathology, 160, 1921-1935.

[23]   Seidah, N.G. and Chrétien, M. (1999) Proprotein and Prohormone Convertases: A Family of Subtilases Generating Diverse Bioactive Polypeptides. Brain Research, 848, 45-62.

[24]   Zhou, A., Webb, G., Zhu, X. and Steiner, D.F. (1999) Proteolytic Processing in the Secretory Pathway. Journal of Biological Chemistry, 274, 20745-20748.

[25]   Dieni, S., Matsumoto, T., Dekkers, M., Rauskolb, S., Ionescu, M.S., Deogracias, R., Gundelfinger, E.D., Kojima, M., Nestel, S., Frotscher, M. and Barde, Y.A. (2012) BDNF and Its Pro-Peptide Are Stored in Presynaptic Dense Core Vesicles in Brain Neurons. The Journal of Cell Biology, 196, 775-788.

[26]   Jessop, D.S. (1999) Review: Central Non-Glucocorticoid Inhibitors of the Hypothalamo-Pituitary-Adrenal Axis. Journal of Endocrinology, 160, 169-180.

[27]   Anastasia, A., Deinhardt, K., Chao, M.V., Will, N.E., Irmady, K., Lee, F.S., Hempstead, B.L. and Bracken, C. (2013) Val66Met Polymorphism of BDNF Alters Prodomain Structure to Induce Neuronal Growth Cone Retraction. Nature Communications, 4, 2490.

[28]   Jeanneteau, F., Deinhardt, K., Miyoshi, G., Bennett, A.M. and Chao, M.V. (2010) The MAP Kinase Phosphatase MKP-1 Regulates BDNF-Induced Axon Branching. Nature Neuroscience, 13, 1373-1379.

[29]   Brondello, J.M., Pouysségur, J. and McKenzie, F.R. (1999) Reduced MAP Kinase Phosphatase-1 Degradation after p42/p44MAPK-Dependent Phosphorylation. Science, 286, 2514-2517.

[30]   Chao, M.V. and Hempstead, B.L. (1995) p75 and Trk: A Two-Receptor System. Trends in Neurosciences, 18, 321-326.

[31]   Hempstead, B.L., Martin-Zanca, D., Kaplan, D.R., Parada, L.F. and Chao, M.V. (1991) High-Affinity NGF Binding Requires Coexpression of the trk Proto-Oncogene and the Low-Affinity NGF Receptor. Nature, 350, 678-683.

[32]   Filbin, M.T. (2003) Myelin-Associated Inhibitors of Axonal Regeneration in the Adult Mammalian CNS. Nature Reviews Neuroscience, 4, 703-713.

[33]   Park, K.J., Grosso, C.A., Aubert, I., Kaplan, D.R. and Miller, F.D. (2010) p75NTR-Dependent, Myelin-Mediated Axonal Degeneration Regulates Neural Connectivity in the Adult Brain. Nature Neuroscience, 13, 559-566.

[34]   McAllister, A.K., Lo, D.C. and Katz, L.C. (1995) Neurotrophins Regulate Dendritic Growth in Developing Visual Cortex. Neuron, 15, 791-803.

[35]   Suzuki, S., Numakawa, T., Shimazu, K., Koshimizu, H., Hara, T., Hatanaka, H., Mei, L., Lu, B. and Kojima, M. (2004) BDNF-Induced Recruitment of TrkB Receptor into Neuronal Lipid Rafts: Roles in Synaptic Modulation. The Journal of Cell Biology, 167, 1205-1215.

[36]   Deinhardt, K., Kim, T., Spellman, D.S., Mains, R.E., Eipper, B.A., Neubert, T.A., Chao, M.V. and Hempstead, B.L. (2011) Neuronal Growth Cone Retraction Relies on Proneurotrophin Receptor Signaling through Rac. Science Signaling, 4, ra82.

[37]   Sun, Y., Lim, Y., Li, F., Liu, S., Lu, J.J., Haberberger, R., Zhong, J.H. and Zhou, X.F. (2012) ProBDNF Collapses Neurite Outgrowth of Primary Neurons by Activating RhoA. PLoS One, 7, 35883.

[38]   Cabelli, R.J., Hohn, A. and Shatz, C.J. (1995) Inhibition of Ocular Dominance Column Formation by Infusion of NT-4/5 or BDNF. Science, 267, 1662-1666.

[39]   Tyler, W.J. and Pozzo-Miller, L.D. (2001) BDNF Enhances Quantal Neurotransmitter Release and Increases the Number of Docked Vesicles at the Active Zones of Hippocampal Excitatory Synapses. The Journal of Neuroscience, 21, 4249-4958.

[40]   Ji, Y., Pang, P.T., Feng, L. and Lu, B. (2005) Cyclic AMP Controls BDNF-Induced TrkB Phosphorylation and Dendritic Spine Formation in Mature Hippocampal Neurons. Nature Neuroscience, 8, 164-172.

[41]   Michalski, B. and Fahnestock, M. (2003) Pro-Brain-Derived Neurotrophic Factor Is Decreased in Parietal Cortex in Alzheimer’s Disease. Molecular Brain Research, 111, 148-154.

[42]   Skeldal, S., Matusica, D., Nykjaer, A. and Coulson, E.J. (2011) Proteolytic Processing of the p75 Neurotrophin Receptor: A Prerequisite for Signalling? Neuronal Life, Growth and Death Signalling Are Crucially Regulated by Intra-Membrane Proteolysis and Trafficking of p75NTR. BioEssays, 33, 614-625.

[43]   Woo, N.H., Teng, H.K., Siao, C.J., Chiaruttini, C., Pang, P.T., Milner, T.A., Hempstead, B.L. and Lu, B. (2005) Activation of p75NTR by ProBDNF Facilitates Hippocampal Long-Term Depression. Nature Neuroscience, 8, 1069-1077.

[44]   Nagappan, G., Zaitsev, E., Senatorov, V.V., Yang, J., Hempstead, B.L. and Lu, B. (2009) Control of Extracellular Cleavage of ProBDNF by High Frequency Neuronal Activity. Proceedings of the National Academy of Sciences of the United States of America, 106, 1267-1272.

[45]   Lessmann, V. and Brigadski, T. (2009) Mechanisms, Locations, and Kinetics of Synaptic BDNF Secretion: An Update. Neuroscience Research, 65, 11-22.

[46]   Holm, M.M., Nieto-Gonzalez, J.L., Vardya, I., Vaegter, C.B., Nykjaer, A. and Jensen, K. (2009) Mature BDNF, but Not ProBDNF, Reduces Excitability of Fast-Spiking Interneurons in Mouse Dentate Gyrus. The Journal of Neuroscience, 29, 12412-12418.

[47]   Chevaleyre, V. and Castillo, P.E. (2003) Heterosy-naptic LTD of Hippocampal GABAergic Synapses: A Novel Role of Endocannabinoids in Regulating Excitability. Neuron, 38, 461-472.

[48]   Patterson, S.L., Abel, T., Deuel, T.A., Martin, K.C., Rose, J.C. and Kandel, E.R. (1996) Recombinant BDNF Rescues Deficits in Basal Synaptic Transmission and Hippocampal LTP in BDNF Knockout Mice. Neuron, 16, 1137-1145.

[49]   Korte, M., Carroll, P., Wolf, E., Brem, G., Thoenen, H. and Bonhoeffer, T. (1995) Hippocampal Long-Term Potentiation Is Impaired in Mice Lacking Brain-Derived Neurotrophic Factor. Proceedings of the National Academy of Sciences of the United States of America, 92, 8856-8860.

[50]   Figurov, A., Pozzo-Miller, L.D., Olafsson, P., Wang, T. and Lu, B. (1996) Regulation of Synaptic Responses to High-Frequency Stimulation and LTP by Neurotrophins in the Hippocampus. Nature, 381, 706-709.

[51]   Gottschalk, W.A., Jiang, H., Tartaglia, N., Feng, L., Figurov, A. and Lu, B. (1999) Signaling Mechanisms Mediating BDNF Modulation of Synaptic Plasticity in the Hippocampus. Learning & Memory, 6, 243-256.

[52]   Jovanovic, J.N., Czernik, A.J., Fienberg, A.A., Greengard, P. and Sihra, T.S. (2000) Synapsins as Mediators of BDNF-Enhanced Neurotransmitter Release. Nature Neuroscience, 3, 323-329.

[53]   Pozzo-Miller, L.D., Gottschalk, W., Zhang, L., McDermott, K., Du, J., Gopalakrishnan, R., Oho, C., Sheng, Z.H. and Lu, B. (1999) Impairments in High-Frequency Transmission, Synaptic Vesicle Docking, and Synaptic Protein Distribution in the Hippocampus of BDNF Knockout Mice. The Journal of Neuroscience, 19, 4972-4983.

[54]   Chen, G., Kolbeck, R., Barde, Y.A., Bonhoeffer, T. and Kossel, A. (1999) Relative Contribution of Endogenous Neurotrophins in Hippocampal Long-Term Potentiation. The Journal of Neuroscience, 19, 7983-7990.

[55]   Kang, H., Welcher, A.A., Shelton, D. and Schuman, E.M. (1997) Neurotrophins and Time: Different Roles for TrkB Signaling in Hippocampal Long-Term Potentiation. Neuron, 19, 653-664.

[56]   Kovalchuk, Y., Hanse, E., Kafitz, K.W. and Konnerth, A. (2002) Postsynaptic Induction of BDNF-Mediated Long-Term Potentiation. Science, 295, 1729-1734.

[57]   Levine, E.S., Crozier, R.A., Black, I.B. and Plummer, M.R. (1998) Brain-Derived Neurotrophic Factor Modulates Hippocampal Synaptic Transmission by Increasing N-Methyl-D-Aspartic Acid Receptor Activity. Proceedings of the National Academy of Sciences of the United States of America, 95, 10235-10239.

[58]   Korte, M., Kang, H., Bonhoeffer, T. and Schuman, E. (1998) A Role for BDNF in the Late-Phase of Hippocampal Long-Term Potentiation. Neuropharmacology, 37, 553-559.

[59]   Pang, P.T., Teng, H.K., Zaitsev, E., Woo, N.T., Sakata, K., Zhen, S., Teng, K.K., Yung, W.H., Hempstead, B.L. and Lu, B. (2004) Cleavage of ProBDNF by tPA/Plasmin Is Essential for Long-Term Hippocampal Plasticity. Science, 306, 487-491.

[60]   Minichiello, L., Calella, A.M., Medina, D.L., Bonhoeffer, T., Klein, R. and Korte, M. (2002) Mechanism of TrkB-Mediated Hippocampal Long-Term Potentiation. Neuron, 36, 121-137.

[61]   Patterson, S.L., Grover, L.M., Schwartzkroin, P.A. and Bothwell, M. (1992) Neurotrophin Expression in Rat Hippocampal Slices: A Stimulus Paradigm Inducing LTP in CA1 Evokes Increases in BDNF and NT-3 mRNAs. Neuron, 9, 1081-1088.

[62]   Castrén, E., Pitkänen, M., Sirviö, J., Parsadanian, A., Lindholm, D., Thoenen, H. and Riekkinen, P.J. (1993) The Induction of LTP Increases BDNF and NGF mRNA but Decreases NT-3 mRNA in the Dentate Gyrus. NeuroReport, 4, 895-898.

[63]   Silhol, M., Arancibia, S., Maurice, T. and Tapia-Arancibia, L. (2007) Spatial Memory Training Modifies the Expression of Brain-Derived Neurotrophic Factor Tyrosine Kinase Receptors in Young and Aged Rats. Neuroscience, 146, 962-973.

[64]   Tongiorgi, E., Righi, M. and Cattaneo, A. (1997) Activity-Dependent Dendritic Targeting of BDNF and TrkB mRNAs in Hippocampal Neurons. Journal of Neuroscience, 17, 9492-9505.

[65]   Simonato, M., Bregola, G., Armellin, M., Del Piccolo, P., Rodi, D., Zucchini, S. and Tongiorgi, E. (2002) Dendritic Targeting of mRNAs for Plasticity Genes in Experimental Models of Temporal Lobe Epilepsy. Epilepsia, 43, 153-158.

[66]   Chiaruttini, C., Sonego, M., Baj, G., Simonato, M. and Tongiorgi, E. (2008) BDNF mRNA Splice Variants Display Activity-Dependent Targeting to Distinct Hippocampal Laminae. Molecular and Cellular Neuroscience, 37, 11-19.

[67]   Kang, H. and Schuman, E.M. (1995) Long-Lasting Neurotrophin-Induced Enhancement of Synaptic Transmission in the Adult Hippocampus. Science, 267, 1658-1662.

[68]   Kang, H. and Schuman, E.M. (1996) A Requirement for Local Protein Synthesis in Neurotrophin-Induced Hippocampal Synaptic Plasticity. Science, 273, 1402-1406.

[69]   Aakalu, G., Smith, W.B., Nguyen, N., Jiang, C. and Schuman, E.M. (2001) Dynamic Visualization of Local Protein Synthesis in Hippocampal Neurons. Neuron, 30, 489-502.

[70]   Schratt, G.M., Nigh, E.A., Chen, W.G., Hu, L. and Greenberg, M.E. (2004) BDNF Regulates the Translation of a Select Group of mRNAs by a Mammalian Target of Rapamycin-Phosphatidylinositol 3-Kinase-Dependent Pathway during Neuronal Development. The Journal of Neuroscience, 24, 7366-7377.

[71]   Schratt, G.M., Tuebing, F., Nigh, E.A., Kane, C.G., Sabatini, M.E., Kiebler, M. and Greenberg, M.E. (2006) A Brain-Specific MicroRNA Regulates Dendritic Spine Development. Nature, 439, 283-289.

[72]   Takei, N., Inamura, N., Kawamura, M., Namba, H., Hara, K., Yonezawa, K. and Nawa, H. (2004) Brain-Derived Neurotrophic Factor induces Mammalian Target of Rapamycin-Dependent Local Activation of Translation Machinery and Protein Synthesis in Neuronal Dendrites. The Journal of Neuroscience, 24, 9760-9769.

[73]   Yin, Y., Edelman, G.M. and Vanderklish, P.W. (2002) The Brain-Derived Neurotrophic Factor Enhances Synthesis of Arc in Synaptoneurosomes. Proceedings of the National Academy of Sciences of the United States of America, 99, 2368-2373.

[74]   Timmusk, T., Palm, K., Metsis, M., Reintam, T., Paalme, V., Saarma, M. and Persson, H. (1993) Multiple Promoters Direct Tissue-Specific Expression of the Rat BDNF Gene. Neuron, 10, 475-489.

[75]   Aid, T., Kazantseva, A., Piirsoo, M., Palm, K. and Timmusk, T. (2007) Mouse and Rat BDNF Gene Structure and Expression Revisited. The Journal of Neuroscience Research, 85, 525-535.

[76]   Pruunsild, P., Kazantseva, A., Aid, T., Palm, K. and Timmusk, T. (2007) Dissecting the Human BDNF Locus: Bidirectional Transcription, Complex Splicing, and Multiple Promoters. Genomics, 90, 397-406.

[77]   Tao, X., West, A.E., Chen, W.G., Corfas, G. and Greenberg, M.E. (2002) A Calcium-Responsive Transcription Factor, CaRF, That Regulates Neuronal Activity-Dependent Expression of BDNF. Neuron, 33, 383-395.

[78]   Metsis, M., Timmusk, T., Arenas, E. and Persson, H. (1993) Differential Usage of Multiple Brain-Derived Neurotrophic Factor Promoters in the Rat Brain Following Neuronal Activation. Proceedings of the National Academy of Sciences of the United States of America, 90, 8802-8806.

[79]   Hong, E.J., McCord, A.E. and Greenberg, M.E. (2008) A Biological Function for the Neuronal Activity-Dependent Component of Bdnf Transcription in the Development of Cortical Inhibition. Neuron, 60, 610-624.

[80]   Sakata, K., Woo, N.H., Martinowich, K., Greene, J.S., Schloesser, R.J., Shen, L. and Lu, B. (2009) Critical Role of Promoter IV-Driven BDNF Transcription in GABAergic Transmission and Synaptic Plasticity in the Prefrontal Cortex. Proceedings of the National Academy of Sciences of the United States of America, 106, 5942-5947.

[81]   Pruunsild, P., Sepp, M., Orav, E., Koppel, I. and Timmusk, T. (2011) Identification of Cis-Elements and Transcription Factors Regulating Neuronal Activity-Dependent Transcription of Human BDNF Gene. The Journal of Neuroscience, 31, 3295-3308.

[82]   An, J.J., Gharami, K., Liao, G.Y., Woo, N.H., Lau, A.G., Vanevski, F., Torre, E.R., Jones, K.R., Feng, Y., Lu, B. and Xu, B. (2008) Distinct Role of Long 3’UTR BDNF mRNA in Spine Morphology and Synaptic Plasticity in Hippocampal Neurons. Cell, 134, 175-187.

[83]   Baj, G., Leone, E., Chao, M.V. and Tongiorgi, E. (2011) Spatial Segregation of BDNF Transcripts Enables BDNF to Differentially Shape Distinct Dendritic Compartments. Proceedings of the National Academy of Sciences of the United States of America, 108, 16813-16818.

[84]   Mahmoudi, S., Henriksson, S., Corcoran, M., Méndez-Vidal, C., Wiman, K.G. and Farnebo, M. (2009) Wrap53, A Natural p53 Antisense Transcript Required for p53 Induction upon DNA Damage. Molecular Cell, 33, 462-471.

[85]   Faghihi, M.A., Modarresi, F., Khalil, A.M., Wood, D.E., Sahagan, B.G., Morgan, T.E., Finch, C.E., St Laurent 3rd., G., Kenny, P.J. and Wahlestedt, C. (2008) Expression of a Noncoding RNA Is Elevated in Alzheimer’s Disease and Drives Rapid Feed-Forward Regulation of Beta-Secretase. Nature Medicine, 14, 723-730.

[86]   Modarresi, F., Faghihi, M.A., Lopez-Toledano, M.A., Fatemi, R.P., Magistri, M., Brothers, S.P., Van der Brug, M.P. and Wahlestedt, C. (2012) Inhibition of Natural Antisense Transcripts in Vivo Results in Gene-Specific Transcriptional Upregulation. Nature Biotechnology, 30, 453-459.

[87]   Peter, C.J. and Akbarian, S. (2011) Balancing Histone Methylation Activities in Psychiatric Disorders. Trends in Molecular Medicine, 17, 372-379.

[88]   Barker, P.A. (2009) Whither ProBDNF? Nature Neuroscience, 12, 105-106.

[89]   Greenberg, M.E., Xu, B., Lu, B. and Hempstead, B.L. (2009) New Insights in the Biology of BDNF Synthesis and Release: Implications in CNS Function. The Journal of Neuroscience, 29, 12764-12767.

[90]   Matsumoto, T., Rauskolb, S., Polack, M., Klose, J., Kolbeck, R., Korte, M. and Barde, Y.A. (2008) Biosynthesis and Processing of Endogenous BDNF: CNS Neurons Store and Secrete BDNF, Not Pro-BDNF. Nature Neuroscience, 11, 131-133.

[91]   Yang, F., Je, H.S., Ji, Y., Nagappan, G., Hempstead, B. and Lu, B. (2009) Pro-BDNF-Induced Synaptic Depression and Retraction at Developing Neuromuscular Synapses. The Journal of Cell Biology, 185, 727-741.

[92]   Kohara, K., Kitamura, A., Morishima, M. and Tsumoto, T. (2001) Activity-Dependent Transfer of Brain-Derived Neurotrophic Factor to Postsynaptic Neurons. Science, 291, 2419-2423.

[93]   Suter, U., Heymach, J.V. and Shooter, E.M. (1991) Two Conserved Domains in the NGF Propeptide Are Necessary and Sufficient for the Biosynthesis of Correctly Processed and Biologically Active NGF. The EMBO Journal, 10, 2395-2400.

[94]   Rattenholl, A., Ruoppolo, M., Flagiello, A., Monti, M., Vinci, F., Marino, G., Lilie, H., Schwarz, E. and Rudolph, R. (2001) Pro-Sequence Assisted Folding and Disulfide Bond Formation of Human Nerve Growth Factor. Journal of Molecular Biology, 305, 523-533.

[95]   Chen, Z.Y., Patel, P.D., Sant, G., Meng, C.X., Teng, K.K., Hempstead, B.L. and Lee, F.S. (2004) Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons. The Journal of Neuroscience, 24, 4401-4411.

[96]   Lou, H., Kim, S.K., Zaitsev, E., Snell, C.R., Lu, B. and Loh, Y.P. (2005) Sorting and Activity-Dependent Secretion of BDNF Require Interaction of a Specific Motif with the Sorting Receptor Carboxypeptidase. Neuron, 45, 245-255.

[97]   Chen, Z.Y., Ieraci, A., Teng, H., Dall, H., Meng, C.X., Herrera, D.G., Nykjaer, A., Hempstead, B.L. and Lee, F.S. (2005) Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway. The Journal of Neuroscience, 25, 6156-6166.

[98]   Rattenholl, A., Lilie, H., Grossmann, A., Stern, A., Schwarz, E. and Rudolph, R. (2001) The Pro-Sequence Facilitates Folding of Human Nerve Growth Factor from Escherichia Coli Inclusion Bodies. European Journal of Biochemistry, 268, 3296-3303.

[99]   Toyooka, K., Asama, K., Watanabe, Y., Muratake, T., Takahashi, M., Someya, T. and Nawa, H. (2002) Decreased Levels of Brain-Derived Neurotrophic Factor in Serum of Chronic Schizophrenic Patients. Psychiatry Research, 110, 249-257.

[100]   Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G. and Aubry, J.M. (2002) Decreased Serum Brain-Derived Neurotrophic Factor Levels in Major Depressed Patients. Psychiatry Research, 109, 143-148.

[101]   Shimizu, E., Hashimoto, K., Okamura, N., Koike, K., Komatsu, N., Kumakiri, C., Nakazato, M., Watanabe, H., Shinoda, N., Okada, S. and Iyo, M. (2003) Alterations of Serum Levels of Brain-Derived Neurotrophic Factor (BDNF) in Depressed Patients with or without Antidepressants. Biological Psychiatry, 54, 70-75.

[102]   Sen, S., Duman, R. and Sanacora, G. (2008) Serum Brain-Derived Neurotrophic Factor, Depression, and Antidepressant Medications: Meta-Analyses and Implications. Biological Psychiatry, 64, 527-532.

[103]   Matsuoka, Y., Nishi, D., Noguchi, H., Kim, Y. and Hashimoto, K. (2013) Longitudinal Changes in Serum Brain-Derived Neurotrophic Factor in Accident Survivors with Posttraumatic Stress Disorder. Neuropsychobiology, 68, 44-50.

[104]   Dell’Osso, L., Carmassi, C., Del Debbio, A., Catena Dell’Osso, M., Bianchi, C., Da Pozzo, E., Origlia, N., Domenici, L., Massimetti, G., Marazziti, D. and Piccinni, A. (2009) Brain-Derived Neurotrophic Factor Plasma Levels in Patients Suffering from Post-Traumatic Stress Disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 899-902.

[105]   Fujimura, H., Altar, C.A., Chen, R., Nakamura, T., Nakahashi, T., Kambayashi, J., Sun, B. and Tandon, N.N. (2002) Brain-Derived Neurotrophic Factor Is Stored in Human Platelets and Released by Agonist Stimulation. Thrombosis and Haemostasis, 87, 728-734.

[106]   Lee, B.H. and Kim, Y.K. (2009) Reduced Platelet BDNF Level in Patients with Major Depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 849-853.

[107]   Molendijk, M.L., Haffmans, J.P., Bus, B.A., Spinhoven, P., Penninx, B.W., Prickaerts, J., Oude Voshaar, R.C. and Elzinga, B.M. (2012) Serum BDNF Concentrations Show Strong Seasonal Variation and Correlations with the Amount of Ambient Sunlight. PLoS One, 7, 48046.