Neurotrophin Signaling and Stem Cells—Implications for Neurodegenerative Diseases and Stem Cell Therapy

Abstract

Neurotrophins (NTs) are members of a neuronal growth factor protein family whose action is mediated by the tropomyosin receptor kinase (TRK) receptor family receptors and the p75 NT receptor (p75NTR), a member of the tumor necrosis factor (TNF) receptor family. Although NTs were first discovered in neurons, recent studies have suggested that NTs and their receptors are expressed in various types of stem cells mediating pivotal signaling events in stem cell biology. The concept of stem cell therapy has already attracted much attention as a potential strategy for the treatment of neurodegenerative diseases (NDs). Strikingly, NTs, proNTs, and their receptors are gaining interest as key regulators of stem cells differentiation, survival, self-renewal, plasticity, and migration. In this review, we elaborate the recent progress in understanding of NTs and their action on various stem cells. First, we provide current knowledge of NTs, proNTs, and their receptor isoforms and signaling pathways. Subsequently, we describe recent advances in the understanding of NT activities in various stem cells and their role in NDs, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD). Finally, we compile the implications of NTs and stem cells from a clinical perspective and discuss the challenges with regard to transplantation therapy for treatment of AD and PD.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. 1.

    Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276(16):12660–12666. doi:10.1074/jbc.M008104200

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361(1473):1545–1564. doi:10.1098/rstb.2006.1894

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14(1):7–23. doi:10.1038/nrn3379

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Edelmann E, Cepeda-Prado E, Franck M, Lichtenecker P, Brigadski T, Lessmann V (2015) Theta burst firing recruits BDNF release and signaling in postsynaptic CA1 neurons in spike-timing-dependent LTP. Neuron 86(4):1041–1054. doi:10.1016/j.neuron.2015.04.007

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Cohen S, Levi-Montalcini R, Hamburger V (1954) A nerve growth-stimulating factor isolated from sarcom as 37 and 180. Proc Natl Acad Sci U S A 40(10):1014–1018

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Lessmann V, Gottmann K, Malcangio M (2003) Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 69(5):341–374. doi:10.1016/S0301-0082(03)00019-4

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237(4819):1154–1162

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Arevalo JC, Wu SH (2006) Neurotrophin signaling: many exciting surprises! Cell Mol Life Sci 63(13):1523–1537. doi:10.1007/s00018-006-6010-1

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Hempstead BL (2014) Deciphering proneurotrophin actions. Handb Exp Pharmacol 220:17–32. doi:10.1007/978-3-642-45106-5_2

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Nykjaer A, Willnow TE (2012) Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci 35(4):261–270. doi:10.1016/j.tins.2012.01.003

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Willnow TE, Petersen CM, Nykjaer A (2008) VPS10P-domain receptors—regulators of neuronal viability and function. Nat Rev Neurosci 9(12):899–909. doi:10.1038/nrn2516

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Gotz R, Koster R, Winkler C, Raulf F, Lottspeich F, Schartl M, Thoenen H (1994) Neurotrophin-6 is a new member of the nerve growth factor family. Nature 372(6503):266–269. doi:10.1038/372266a0

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Lai KO, Fu WY, Ip FC, Ip NY (1998) Cloning and expression of a novel neurotrophin, NT-7, from carp. Mol Cell Neurosci 11(1-2):64–76. doi:10.1006/mcne.1998.0666

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Nilsson AS, Fainzilber M, Falck P, Ibanez CF (1998) Neurotrophin-7: a novel member of the neurotrophin family from the zebrafish. FEBS Lett 424(3):285–290. doi:10.1016/S0014-5793(98)00192-6

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Berkemeier LR, Ozcelik T, Francke U, Rosenthal A (1992) Human chromosome 19 contains the neurotrophin-5 gene locus and three related genes that may encode novel acidic neurotrophins. Somat Cell Mol Genet 18(3):233–245. doi:10.1007/BF01233860

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A 78(12):7634–7638

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Klimanskaya I, Rosenthal N, Lanza R (2008) Derive and conquer: sourcing and differentiating stem cells for therapeutic applications. Nat Rev Drug Discov 7(2):131–142. doi:10.1038/nrd2403

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Goodell MA, Nguyen H, Shroyer N (2015) Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. Nat Rev Mol Cell Biol 16(5):299–309. doi:10.1038/nrm3980

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Wobus AM, Boheler KR (2005) Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol Rev 85(2):635–678. doi:10.1152/physrev.00054.2003

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Zhu Z, Huangfu D (2013) Human pluripotent stem cells: an emerging model in developmental biology. Development 140(4):705–717. doi:10.1242/dev.086165

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Rookmaaker MB, Schutgens F, Verhaar MC, Clevers H (2015) Development and application of human adult stem or progenitor cell organoids. Nat Rev Nephrol 11(9):546–554. doi:10.1038/nrneph.2015.118

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66(9):4553–4557. doi:10.1158/0008-5472.CAN-05-3986

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Lotem J, Sachs L (2006) Epigenetics and the plasticity of differentiation in normal and cancer stem cells. Oncogene 25(59):7663–7672. doi:10.1038/sj.onc.1209816

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Okita K, Yamanaka S (2011) Induced pluripotent stem cells: opportunities and challenges. Philos Trans R Soc Lond B Biol Sci 366(1575):2198–2207. doi:10.1098/rstb.2011.0016

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Yamanaka S (2012) Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10(6):678–684. doi:10.1016/j.stem.2012.05.005

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Tomellini E, Lagadec C, Polakowska R, Le Bourhis X (2014) Role of p75 neurotrophin receptor in stem cell biology: more than just a marker. Cell Mol Life Sci 71(13):2467–2481. doi:10.1007/s00018-014-1564-9

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Lu P, Jones LL, Snyder EY, Tuszynski MH (2003) Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 181(2):115–129. doi:10.1016/S0014-4886(03)00037-2

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Pyle AD, Lock LF, Donovan PJ (2006) Neurotrophins mediate human embryonic stem cell survival. Nat Biotechnol 24(3):344–350. doi:10.1038/nbt1189

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Levi-Montalcini R, Hamburger V (1953) A diffusible agent of mouse sarcoma, producing hyperplasia of sympathetic ganglia and hyperneurotization of viscera in the chick embryo. J Exp Zool 123(2):233–287. doi:10.1002/jez.1401230203

    Article  Google Scholar 

  32. 32.

    Cohen S, Levi-Montalcini R (1956) A nerve growth-stimulating factor isolated from snake venom. Proc Natl Acad Sci U S A 42(9):571–574

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Tischler AS, Riseberg JC, Hardenbrook MA, Cherington V (1993) Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro. J Neurosci 13(4):1533–1542

    CAS  PubMed  Google Scholar 

  34. 34.

    Misko TP, Radeke MJ, Shooter EM (1987) Nerve growth factor in neuronal development and maintenance. J Exp Biol 132:177–190

    CAS  PubMed  Google Scholar 

  35. 35.

    Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24:1217–1281. doi:10.1146/annurev.neuro.24.1.1217

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Scott SA, Mufson EJ, Weingartner JA, Skau KA, Crutcher KA (1995) Nerve growth factor in Alzheimer’s disease: increased levels throughout the brain coupled with declines in nucleus basalis. J Neurosci 15(9):6213–6221

    CAS  PubMed  Google Scholar 

  37. 37.

    Lorigados Pedre L, Pavon Fuentes N, Alvarez Gonzalez L, McRae A, Serrano Sanchez T, Blanco Lescano L, Macias Gonzalez R (2002) Nerve growth factor levels in Parkinson disease and experimental parkinsonian rats. Brain Res 952(1):122–127. doi:10.1016/S0006-8993(02)03222-5

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Shamini Ayyadhury BSP, Klaus Heese BSP (2007) Neurotrophins—more than neurotrophic. Curr Immunol Rev 3(3):189–215. doi:10.2174/157339507781483504

    Article  Google Scholar 

  39. 39.

    Heese K, Inoue N, Sawada T (2006) NF-kappaB regulates B-cell-derived nerve growth factor expression. Cell Mol Immunol 3(1):63–66

    CAS  PubMed  Google Scholar 

  40. 40.

    Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli L, Leon A (1996) Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci 19(11):514–520. doi:10.1016/S0166-2236(96)10058-8

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Indo Y (2014) Neurobiology of pain, interoception and emotional response: lessons from nerve growth factor-dependent neurons. Eur J Neurosci 39(3):375–391. doi:10.1111/ejn.12448

    PubMed  Article  Google Scholar 

  42. 42.

    Lewin GR, Nykjaer A (2014) Pro-neurotrophins, sortilin, and nociception. Eur J Neurosci 39(3):363–374. doi:10.1111/ejn.12466

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Torcia M, Bracci-Laudiero L, Lucibello M et al (1996) Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell 85(3):345–356. doi:10.1016/S0092-8674(00)81113-7

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Einarsdottir E, Carlsson A, Minde J et al (2004) A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 13(8):799–805. doi:10.1093/hmg/ddh096

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Hallbook F (1999) Evolution of the vertebrate neurotrophin and Trk receptor gene families. Curr Opin Neurobiol 9(5):616–621. doi:10.1016/S0959-4388(99)00011-2

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Ullrich A, Gray A, Berman C, Dull TJ (1983) Human beta-nerve growth factor gene sequence highly homologous to that of mouse. Nature 303(5920):821–825

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Fahnestock M, Yu G, Coughlin MD (2004) ProNGF: a neurotrophic or an apoptotic molecule? Prog Brain Res 146:101–110. doi:10.1016/S0079-6123(03)46007-X

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Darling TL, Petrides PE, Beguin P, Frey P, Shooter EM, Selby M, Rutter WJ (1983) The biosynthesis and processing of proteins in the mouse 7S nerve growth factor complex. Cold Spring Harb Symp Quant Biol 48(Pt 1):427–434

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Garzon D, Yu G, Fahnestock M (2004) A new brain-derived neurotrophic factor transcript and decrease inbrain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex. J Neurochem 82(5):1058–1064. doi:10.1046/j.1471-4159.2002.01030.x

    Article  Google Scholar 

  50. 50.

    Seidah NG, Benjannet S, Pareek S, Chretien M, Murphy RA (1996) Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 379(3):247–250

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294(5548):1945–1948. doi:10.1126/science.1065057

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Fahnestock M, Michalski B, Xu B, Coughlin MD (2001) The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer’s disease. Mol Cell Neurosci 18(2):210–220. doi:10.1006/mcne.2001.1016

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Yepes M, Lawrence DA (2004) Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system? Trends Cardiovasc Med 14(5):173–180. doi:10.1016/j.tcm.2004.03.004

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Iulita MF, Cuello AC (2014) Nerve growth factor metabolic dysfunction in Alzheimer’s disease and Down syndrome. Trends Pharmacol Sci 35(7):338–348. doi:10.1016/j.tips.2014.04.010

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Miranda E, Lomas DA (2006) Neuroserpin: a serpin to think about. Cell Mol Life Sci 63(6):709–722. doi:10.1007/s00018-005-5077-4

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Bradshaw RA, Murray-Rust J, Ibanez CF, McDonald NQ, Lapatto R, Blundell TL (1994) Nerve growth factor: structure/function relationships. Protein Sci 3(11):1901–1913. doi:10.1002/pro.5560031102

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Bax B, Blundell TL, Murray-Rust J, McDonald NQ (1997) Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins. Structure 5(10):1275–1285. doi:10.1016/S0969-2126(97)00280-3

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Freund-Michel V, Frossard N (2008) The nerve growth factor and its receptors in airway inflammatory diseases. Pharmacol Ther 117(1):52–76. doi:10.1016/j.pharmthera.2007.07.003

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Eibl JK, Strasser BC, Ross GM (2012) Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int 61(8):1266–1275. doi:10.1016/j.neuint.2012.10.008

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Robinson RC, Radziejewski C, Stuart DI, Jones EY (1995) Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer. Biochemistry 34(13):4139–4146

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Feng D, Kim T, Ozkan E, Light M, Torkin R, Teng KK, Hempstead BL, Garcia KC (2010) Molecular and structural insight into proNGF engagement of p75NTR and sortilin. J Mol Biol 396(4):967–984. doi:10.1016/j.jmb.2009.12.030

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1(5):549–553

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Barde YA, Davies AM, Johnson JE, Lindsay RM, Thoenen H (1987) Brain derived neurotrophic factor. Prog Brain Res 71:185–189

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H, Barde YA (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341(6238):149–152. doi:10.1038/341149a0

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 70(5):271–288. doi:10.1002/dneu.20774

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10(3):209–219. doi:10.1038/nrd3366

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Ohira K, Hayashi M (2009) A new aspect of the TrkB signaling pathway in neural plasticity. Curr Neuropharmacol 7(4):276–285. doi:10.2174/157015909790031210

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Zuccato C, Cattaneo E (2009) Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 5(6):311–322. doi:10.1038/nrneurol.2009.54

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 10(4):345–352. doi:10.1038/sj.mp.4001637

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R (2014) Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front Cell Neurosci 8:430. doi:10.3389/fncel.2014.00430

    PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Prakash YS, Martin RJ (2014) Brain-derived neurotrophic factor in the airways. Pharmacol Ther 143(1):74–86. doi:10.1016/j.pharmthera.2014.02.006

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Lee DH, Geyer E, Flach AC, Jung K, Gold R, Flugel A, Linker RA, Luhder F (2012) Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination. Acta Neuropathol 123(2):247–258. doi:10.1007/s00401-011-0890-3

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T (2007) Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 90(3):397–406. doi:10.1016/j.ygeno.2007.05.004

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Negro A, Tavella A, Grandi C, Skaper SD (1994) Production and characterization of recombinant rat brain-derived neurotrophic factor and neurotrophin-3 from insect cells. J Neurochem 62(2):471–478

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Harte-Hargrove LC, Maclusky NJ, Scharfman HE (2013) Brain-derived neurotrophic factor-estrogen interactions in the hippocampal mossy fiber pathway: implications for normal brain function and disease. Neuroscience 239:46–66. doi:10.1016/j.neuroscience.2012.12.029

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Mowla SJ, Pareek S, Farhadi HF et al (1999) Differential sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons. J Neurosci 19(6):2069–2080

    CAS  PubMed  Google Scholar 

  77. 77.

    Faria RS, Sartori CR, Canova F, Ferrari EA (2013) Classical aversive conditioning induces increased expression of mature-BDNF in the hippocampus and amygdala of pigeons. Neuroscience 255:122–133. doi:10.1016/j.neuroscience.2013.09.054

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Carlino D, De Vanna M, Tongiorgi E (2013) Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions? Neuroscientist 19(4):345–353. doi:10.1177/1073858412469444

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Nagappan G, Zaitsev E, Senatorov VV Jr, Yang J, Hempstead BL, Lu B (2009) Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc Natl Acad Sci U S A 106(4):1267–1272. doi:10.1073/pnas.0807322106

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Pang PT, Teng HK, Zaitsev E et al (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306(5695):487–491. doi:10.1126/science.1100135

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Robinson RC, Radziejewski C, Spraggon G et al (1999) The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci 8(12):2589–2597. doi:10.1110/ps.8.12.2589

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM, Yancopoulos GD (1990) Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 247(4949 Pt 1):1446–1451

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Chalazonitis A (1996) Neurotrophin-3 as an essential signal for the developing nervous system. Mol Neurobiol 12(1):39–53. doi:10.1007/BF02740746

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Maisonpierre PC, Le Beau MM, Espinosa R 3rd et al (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10(3):558–568

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Chalazonitis A (2004) Neurotrophin-3 in the development of the enteric nervous system. Prog Brain Res 146:243–263. doi:10.1016/S0079-6123(03)46016-0

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R (1999) Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci 2(2):115–117. doi:10.1038/5669

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Lykissas MG, Batistatou AK, Charalabopoulos KA, Beris AE (2007) The role of neurotrophins in axonal growth, guidance, and regeneration. Curr Neurovasc Res 4(2):143–151

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Roh J, Muelleman T, Tawfik O, Thomas SM (2015) Perineural growth in head and neck squamous cell carcinoma: a review. Oral Oncol 51(1):16–23. doi:10.1016/j.oraloncology.2014.10.004

    PubMed  Article  Google Scholar 

  89. 89.

    Tauszig-Delamasure S, Bouzas-Rodriguez J (2011) Targeting neurotrophin-3 and its dependence receptor tyrosine kinase receptor C: a new antitumoral strategy. Expert Opin Ther Targets 15(7):847–858. doi:10.1517/14728222.2011.575361

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Yano H, Torkin R, Martin LA, Chao MV, Teng KK (2009) Proneurotrophin-3 is a neuronal apoptotic ligand: evidence for retrograde-directed cell killing. J Neurosci 29(47):14790–14802. doi:10.1523/JNEUROSCI.2059-09.2009

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Farhadi HF, Mowla SJ, Petrecca K, Morris SJ, Seidah NG, Murphy RA (2000) Neurotrophin-3 sorts to the constitutive secretory pathway of hippocampal neurons and is diverted to the regulated secretory pathway by coexpression with brain-derived neurotrophic factor. J Neurosci 20(11):4059–4068

    CAS  PubMed  Google Scholar 

  92. 92.

    Butte MJ, Hwang PK, Mobley WC, Fletterick RJ (1998) Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors. Biochemistry 37(48):16846–16852. doi:10.1021/bi981254o

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Ibanez CF (1996) Neurotrophin-4: the odd one out in the neurotrophin family. Neurochem Res 21(7):787–793

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Berkemeier LR, Winslow JW, Kaplan DR, Nikolics K, Goeddel DV, Rosenthal A (1991) Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron 7(5):857–866

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Koliatsos VE, Cayouette MH, Berkemeier LR, Clatterbuck RE, Price DL, Rosenthal A (1994) Neurotrophin 4/5 is a trophic factor for mammalian facial motor neurons. Proc Natl Acad Sci U S A 91(8):3304–3308

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Zheng JL, Stewart RR, Gao WQ (1995) Neurotrophin-4/5 enhances survival of cultured spiral ganglion neurons and protects them from cisplatin neurotoxicity. J Neurosci 15(7 Pt 2):5079–5087

    CAS  PubMed  Google Scholar 

  97. 97.

    Cohen A, Bray GM, Aguayo AJ (1994) Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro. J Neurobiol 25(8):953–959. doi:10.1002/neu.480250805

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Hondermarck H (2012) Neurotrophins and their receptors in breast cancer. Cytokine Growth Factor Rev 23(6):357–365. doi:10.1016/j.cytogfr.2012.06.004

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Szczepankiewicz A, Rachel M, Sobkowiak P, Kycler Z, Wojsyk-Banaszak I, Schoneich N, Skibinska M, Breborowicz A (2012) Serum neurotrophin-3 and neurotrophin-4 levels are associated with asthma severity in children. Eur Respir J 39(4):1035–1037. doi:10.1183/09031936.00136611

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Aven L, Paez-Cortez J, Achey R, Krishnan R, Ram-Mohan S, Cruikshank WW, Fine A, Ai X (2014) An NT4/TrkB-dependent increase in innervation links early-life allergen exposure to persistent airway hyperreactivity. FASEB J 28(2):897–907. doi:10.1096/fj.13-238212

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Grewe M, Vogelsang K, Ruzicka T, Stege H, Krutmann J (2000) Neurotrophin-4 production by human epidermal keratinocytes: increased expression in atopic dermatitis. J Investig Dermatol 114(6):1108–1112. doi:10.1046/j.1523-1747.2000.00974.x

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Kanda N, Koike S, Watanabe S (2005) Prostaglandin E2 enhances neurotrophin-4 production via EP3 receptor in human keratinocytes. J Pharmacol Exp Ther 315(2):796–804. doi:10.1124/jpet.105.091645

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Yoshizaki K, Yamamoto S, Yamada A et al (2008) Neurotrophic factor neurotrophin-4 regulates ameloblastin expression via full-length TrkB. J Biol Chem 283(6):3385–3391. doi:10.1074/jbc.M704913200

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Wiesmann C, Ultsch MH, Bass SH, de Vos AM (1999) Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Nature 401(6749):184–188. doi:10.1038/43705

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Greco A, Villa R, Pierotti MA (1996) Genomic organization of the human NTRK1 gene. Oncogene 13(11):2463–2466

    CAS  PubMed  Google Scholar 

  106. 106.

    Barker PA, Lomen-Hoerth C, Gensch EM, Meakin SO, Glass DJ, Shooter EM (1993) Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem 268(20):15150–15157

    CAS  PubMed  Google Scholar 

  107. 107.

    Tacconelli A, Farina AR, Cappabianca L et al (2004) TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell 6(4):347–360. doi:10.1016/j.ccr.2004.09.011

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Meakin SO, Gryz EA, MacDonald JI (1997) A kinase insert isoform of rat TrkA supports nerve growth factor-dependent cell survival but not neurite outgrowth. J Neurochem 69(3):954–967

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Dubus P, Parrens M, El-Mokhtari Y, Ferrer J, Groppi A, Merlio JP (2000) Identification of novel trkA variants with deletions in leucine-rich motifs of the extracellular domain. J Neuroimmunol 107(1):42–49

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Jullien J, Guili V, Reichardt LF, Rudkin BB (2002) Molecular kinetics of nerve growth factor receptor trafficking and activation. J Biol Chem 277(41):38700–38708. doi:10.1074/jbc.M202348200

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Zhou J, Valletta JS, Grimes ML, Mobley WC (1995) Multiple levels for regulation of TrkA in PC12 cells by nerve growth factor. J Neurochem 65(3):1146–1156

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Marlin MC, Li G (2015) Biogenesis and function of the NGF/TrkA signaling endosome. Int Rev Cell Mol Biol 314:239–257. doi:10.1016/bs.ircmb.2014.10.002

    PubMed  Article  Google Scholar 

  113. 113.

    Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, Bass SH, de Vos AM (1999) Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC. J Mol Biol 290(1):149–159. doi:10.1006/jmbi.1999.2816

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Urfer R, Tsoulfas P, O’Connell L, Hongo JA, Zhao W, Presta LG (1998) High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors. J Biol Chem 273(10):5829–5840

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Bertrand T, Kothe M, Liu J et al (2012) The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. J Mol Biol 423(3):439–453. doi:10.1016/j.jmb.2012.08.002

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Nikoletopoulou V, Lickert H, Frade JM, Rencurel C, Giallonardo P, Zhang L, Bibel M, Barde YA (2010) Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467(7311):59–63. doi:10.1038/nature09336

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Soppet D, Escandon E, Maragos J et al (1991) The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 65(5):895–903

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Slaugenhaupt SA, Blumenfeld A, Liebert CB et al (1995) The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene. Genomics 25(3):730–732

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736. doi:10.1146/annurev.neuro.24.1.677

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Ninkina N, Grashchuck M, Buchman VL, Davies AM (1997) TrkB variants with deletions in the leucine-rich motifs of the extracellular domain. J Biol Chem 272(20):13019–13025

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Baxter GT, Radeke MJ, Kuo RC et al (1997) Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2. J Neurosci 17(8):2683–2690

    CAS  PubMed  Google Scholar 

  122. 122.

    Stoilov P, Castren E, Stamm S (2002) Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem Biophys Res Commun 290(3):1054–1065. doi:10.1006/bbrc.2001.6301

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Forooghian F, Kojic L, Gu Q, Prasad SS (2001) Identification of a novel truncated isoform of trkB in the kitten primary visual cortex. J Mol Neurosci 17(1):81–88. doi:10.1385/JMN:17:1:81

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Barbacid M (1995) Neurotrophic factors and their receptors. Curr Opin Cell Biol 7(2):148–155

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Feng Y, Vetro A, Kiss E et al (2008) Association of the neurotrophic tyrosine kinase receptor 3 (NTRK3) gene and childhood-onset mood disorders. Am J Psychiatry 165(5):610–616. doi:10.1176/appi.ajp.2007.07050805

    PubMed  Article  Google Scholar 

  126. 126.

    Lamballe F, Klein R, Barbacid M (1991) trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 66(5):967–979

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Lamballe F, Tapley P, Barbacid M (1993) trkC encodes multiple neurotrophin-3 receptors with distinct biological properties and substrate specificities. EMBO J 12(8):3083–3094

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Valenzuela DM, Maisonpierre PC, Glass DJ et al (1993) Alternative forms of rat TrkC with different functional capabilities. Neuron 10(5):963–974

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Tsoulfas P, Soppet D, Escandon E, Tessarollo L, Mendoza-Ramirez JL, Rosenthal A, Nikolics K, Parada LF (1993) The rat trkC locus encodes multiple neurogenic receptors that exhibit differential response to neurotrophin-3 in PC12 cells. Neuron 10(5):975–990

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Radeke MJ, Misko TP, Hsu C, Herzenberg LA, Shooter EM (1987) Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature 325(6105):593–597. doi:10.1038/325593a0

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Huebner K, Isobe M, Chao M et al (1986) The nerve growth-factor receptor gene is at human-chromosome region 17q12-17q22, distal to the chromosome-17 breakpoint in acute leukemias. Proc Natl Acad Sci U S A 83(5):1403–1407. doi:10.1073/pnas.83.5.1403

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309. doi:10.1038/nrn1078

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Kraemer BR, Yoon SO, Carter BD (2014) The biological functions and signaling mechanisms of the p75 neurotrophin receptor. Handb Exp Pharmacol 220:121–164. doi:10.1007/978-3-642-45106-5_6

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Barrett GL (2000) The p75 neurotrophin receptor and neuronal apoptosis. Prog Neurobiol 61(2):205–229. doi:10.1016/S0301-0082(99)00056-8

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    von Schack D, Casademunt E, Schweigreiter R, Meyer M, Bibel M, Dechant G (2001) Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 4(10):977–978. doi:10.1038/nn730

    Article  Google Scholar 

  136. 136.

    Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69(5):737–749

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Poser R, Dokter M, von Bohlen Und Halbach V, Berger SM, Busch R, Baldus M, Unsicker K, von Bohlen Und Halbach O (2015) Impact of a deletion of the full-length and short isoform of p75NTR on cholinergic innervation and the population of postmitotic doublecortin positive cells in the dentate gyrus. Front Neuroanat 9:63. doi:10.3389/fnana.2015.00063

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Sabry MA, Fares M, Folkesson R, Al-Ramadan M, Alabkal J, Al-Kafaji G, Hassan M (2016) Commentary: Impact of a deletion of the full-length and short isoform of p75NTR on cholinergic innervation and the population of postmitotic doublecortin positive cells in the dentate gyrus. Front Neuroanat 10:14. doi:10.3389/fnana.2016.00014

    PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Langevin C, Jaaro H, Bressanelli S, Fainzilber M, Tuffereau C (2002) Rabies virus glycoprotein (RVG) is a trimeric ligand for the N-terminal cysteine-rich domain of the mammalian p75 neurotrophin receptor. J Biol Chem 277(40):37655–37662. doi:10.1074/jbc.M201374200

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Dechant G, Barde YA (2002) The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci 5(11):1131–1136. doi:10.1038/nn1102-1131

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Nykjaer A, Lee R, Teng KK et al (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427(6977):843–848. doi:10.1038/nature02319

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Grob PM, Ross AH, Koprowski H, Bothwell M (1985) Characterization of the human melanoma nerve growth factor receptor. J Biol Chem 260(13):8044–8049

    CAS  PubMed  Google Scholar 

  143. 143.

    Gong Y, Cao P, Yu HJ, Jiang T (2008) Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature 454(7205):789–793. doi:10.1038/nature07089

    CAS  PubMed  Google Scholar 

  144. 144.

    Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35(1):24–35. doi:10.1016/j.tins.2011.06.007

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Skaper SD (2012) The neurotrophin family of neurotrophic factors: an overview. Methods Mol Biol 846:1–12. doi:10.1007/978-1-61779-536-7_1

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Deinhardt K, Chao MV (2014) Trk receptors. Handb Exp Pharmacol 220:103–119. doi:10.1007/978-3-642-45106-5_5

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789. doi:10.1038/378785a0

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW, Lee CM (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc Natl Acad Sci U S A 97(20):11074–11079. doi:10.1073/pnas.190297597

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65(4):391–426

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Vaillant AR, Mazzoni I, Tudan C, Boudreau M, Kaplan DR, Miller FD (1999) Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival. J Cell Biol 146(5):955–966

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Besset V, Scott RP, Ibanez CF (2000) Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase. J Biol Chem 275(50):39159–39166. doi:10.1074/jbc.M006908200

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    Auer M, Hausott B, Klimaschewski L (2011) Rho GTPases as regulators of morphological neuroplasticity. Ann Anat 193(4):259–266. doi:10.1016/j.aanat.2011.02.015

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Hall A, Lalli G (2010) Rho and Ras GTPases in axon growth, guidance, and branching. Cold Spring Harb Perspect Biol 2(2):a001818. doi:10.1101/cshperspect.a001818

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  154. 154.

    Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19(1):1–49. doi:10.1101/gad.1256405

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Khodosevich K, Monyer H (2010) Signaling involved in neurite outgrowth of postnatally born subventricular zone neurons in vitro. BMC Neurosci 11:18. doi:10.1186/1471-2202-11-18

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. 156.

    Schwamborn JC, Puschel AW (2004) The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7(9):923–929. doi:10.1038/nn1295

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Schwartz M (2004) Rho signalling at a glance. J Cell Sci 117(Pt 23):5457–5458. doi:10.1242/jcs.01582

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Chen C, Wirth A, Ponimaskin E (2012) Cdc42: an important regulator of neuronal morphology. Int J Biochem Cell Biol 44(3):447–451. doi:10.1016/j.biocel.2011.11.022

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Azzarelli R, Kerloch T, Pacary E (2014) Regulation of cerebral cortex development by Rho GTPases: insights from in vivo studies. Front Cell Neurosci 8:445. doi:10.3389/fncel.2014.00445

    PubMed  Google Scholar 

  160. 160.

    Nishimura T, Yamaguchi T, Kato K, Yoshizawa M, Nabeshima Y, Ohno S, Hoshino M, Kaibuchi K (2005) PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol 7(3):270–277. doi:10.1038/ncb1227

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    Shepherd TR, Hard RL, Murray AM, Pei D, Fuentes EJ (2011) Distinct ligand specificity of the Tiam1 and Tiam2 PDZ domains. Biochemistry 50(8):1296–1308. doi:10.1021/bi1013613

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Watabe-Uchida M, John KA, Janas JA, Newey SE, Van Aelst L (2006) The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18. Neuron 51(6):727–739. doi:10.1016/j.neuron.2006.07.020

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Ng J, Luo L (2004) Rho GTPases regulate axon growth through convergent and divergent signaling pathways. Neuron 44(5):779–793. doi:10.1016/j.neuron.2004.11.014

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Yamaguchi Y, Katoh H, Yasui H, Mori K, Negishi M (2001) RhoA inhibits the nerve growth factor-induced Rac1 activation through Rho-associated kinase-dependent pathway. J Biol Chem 276(22):18977–18983. doi:10.1074/jbc.M100254200

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Nusser N, Gosmanova E, Zheng Y, Tigyi G (2002) Nerve growth factor signals through TrkA, phosphatidylinositol 3-kinase, and Rac1 to inactivate RhoA during the initiation of neuronal differentiation of PC12 cells. J Biol Chem 277(39):35840–35846. doi:10.1074/jbc.M203617200

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Arakawa Y, Bito H, Furuyashiki T et al (2003) Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons. J Cell Biol 161(2):381–391. doi:10.1083/jcb.200210149

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Shirazi Fard S, Kele J, Vilar M, Paratcha G, Ledda F (2010) Tiam1 as a signaling mediator of nerve growth factor-dependent neurite outgrowth. PLoS One 5(3), e9647. doi:10.1371/journal.pone.0009647

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  168. 168.

    Zhou P, Porcionatto M, Pilapil M et al (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron 55(1):53–68. doi:10.1016/j.neuron.2007.05.030

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG, Der CJ (2002) Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol 4(8):621–625. doi:10.1038/ncb833

    CAS  PubMed  Google Scholar 

  170. 170.

    Kuruvilla R, Ye H, Ginty DD (2000) Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 27(3):499–512

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Zhou Y, Lu TJ, Xiong ZQ (2009) NGF-dependent retrograde signaling: survival versus death. Cell Res 19(5):525–526. doi:10.1038/cr.2009.47

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Niewiadomska G, Mietelska-Porowska A, Mazurkiewicz M (2011) The cholinergic system, nerve growth factor and the cytoskeleton. Behav Brain Res 221(2):515–526. doi:10.1016/j.bbr.2010.02.024

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Madziar B, Shah S, Brock M et al (2008) Nerve growth factor regulates the expression of the cholinergic locus and the high-affinity choline transporter via the Akt/PKB signaling pathway. J Neurochem 107(5):1284–1293. doi:10.1111/j.1471-4159.2008.05681.x

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Markus A, Zhong J, Snider WD (2002) Raf and akt mediate distinct aspects of sensory axon growth. Neuron 35(1):65–76

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    Deckwerth TL, Elliott JL, Knudson CM, Johnson EM Jr, Snider WD, Korsmeyer SJ (1996) BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17(3):401–411

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Lentz SI, Knudson CM, Korsmeyer SJ, Snider WD (1999) Neurotrophins support the development of diverse sensory axon morphologies. J Neurosci 19(3):1038–1048

    CAS  PubMed  Google Scholar 

  177. 177.

    Liu RY, Snider WD (2001) Different signaling pathways mediate regenerative versus developmental sensory axon growth. J Neurosci 21(17):RC164

    CAS  PubMed  Google Scholar 

  178. 178.

    Namikawa K, Honma M, Abe K et al (2000) Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J Neurosci 20(8):2875–2886

    CAS  PubMed  Google Scholar 

  179. 179.

    Culmsee C, Gerling N, Lehmann M, Nikolova-Karakashian M, Prehn JH, Mattson MP, Krieglstein J (2002) Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TrkA and requires the common neurotrophin receptor P75. Neuroscience 115(4):1089–1108

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR (1999) L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401(6754):703–708. doi:10.1038/44378

    CAS  PubMed  Article  Google Scholar 

  181. 181.

    Kim MS, Shutov LP, Gnanasekaran A, Lin Z, Rysted JE, Ulrich JD, Usachev YM (2014) Nerve growth factor (NGF) regulates activity of nuclear factor of activated T-cells (NFAT) in neurons via the phosphatidylinositol 3-kinase (PI3K)-Akt-glycogen synthase kinase 3beta (GSK3beta) pathway. J Biol Chem 289(45):31349–31360. doi:10.1074/jbc.M114.587188

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Bazenet CE, Mota MA, Rubin LL (1998) The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death. Proc Natl Acad Sci U S A 95(7):3984–3989

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Rosario M, Franke R, Bednarski C, Birchmeier W (2007) The neurite outgrowth multiadaptor RhoGAP, NOMA-GAP, regulates neurite extension through SHP2 and Cdc42. J Cell Biol 178(3):503–516. doi:10.1083/jcb.200609146

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Da Silva JS, Medina M, Zuliani C, Di Nardo A, Witke W, Dotti CG (2003) RhoA/ROCK regulation of neuritogenesis via profilin IIa-mediated control of actin stability. J Cell Biol 162(7):1267–1279. doi:10.1083/jcb.200304021

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. 185.

    Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11(3):297–305. doi:10.1016/S0959-4388(00)00211-7

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286(5443):1358–1362. doi:10.1126/science.286.5443.1358

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Mullen LM, Pak KK, Chavez E, Kondo K, Brand Y, Ryan AF (2012) Ras/p38 and PI3K/Akt but not Mek/Erk signaling mediate BDNF-induced neurite formation on neonatal cochlear spiral ganglion explants. Brain Res 1430:25–34. doi:10.1016/j.brainres.2011.10.054

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Kumar V, Zhang MX, Swank MW, Kunz J, Wu GY (2005) Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 25(49):11288–11299. doi:10.1523/JNEUROSCI.2284-05.2005

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M (2005) Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci 25(49):11300–11312. doi:10.1523/JNEUROSCI.2270-05.2005

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Nakazawa T, Tamai M, Mori N (2002) Brain-derived neurotrophic factor prevents axotomized retinal ganglion cell death through MAPK and PI3K signaling pathways. Invest Ophthalmol Vis Sci 43(10):3319–3326

    PubMed  Google Scholar 

  191. 191.

    Hetman M, Cavanaugh JE, Kimelman D, Xia Z (2000) Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20(7):2567–2574

    CAS  PubMed  Google Scholar 

  192. 192.

    Miller JR, Moon RT (1996) Signal transduction through beta-catenin and specification of cell fate during embryogenesis. Genes Dev 10(20):2527–2539

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Hetman M, Hsuan SL, Habas A, Higgins MJ, Xia Z (2002) ERK1/2 antagonizes glycogen synthase kinase-3beta-induced apoptosis in cortical neurons. J Biol Chem 277(51):49577–49584. doi:10.1074/jbc.M111227200

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    Hetman M, Kanning K, Cavanaugh JE, Xia Z (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 274(32):22569–22580. doi:10.1074/jbc.274.32.22569

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    Cohen P, Goedert M (2004) GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov 3(6):479–487. doi:10.1038/nrd1415

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Davies AM, Horton A, Burton LE, Schmelzer C, Vandlen R, Rosenthal A (1993) Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons. J Neurosci 13(11):4961–4967

    CAS  PubMed  Google Scholar 

  197. 197.

    Minichiello L, Casagranda F, Tatche RS, Stucky CL, Postigo A, Lewin GR, Davies AM, Klein R (1998) Point mutation in trkB causes loss of NT4-dependent neurons without major effects on diverse BDNF responses. Neuron 21(2):335–345

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Vadodaria KC, Brakebusch C, Suter U, Jessberger S (2013) Stage-specific functions of the small Rho GTPases Cdc42 and Rac1 for adult hippocampal neurogenesis. J Neurosci 33(3):1179–1189. doi:10.1523/JNEUROSCI.2103-12.2013

    CAS  PubMed  Article  Google Scholar 

  199. 199.

    Luikart BW, Zhang W, Wayman GA, Kwon CH, Westbrook GL, Parada LF (2008) Neurotrophin-dependent dendritic filopodial motility: a convergence on PI3K signaling. J Neurosci 28(27):7006–7012. doi:10.1523/JNEUROSCI.0195-08.2008

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Liot G, Gabriel C, Cacquevel M, Ali C, MacKenzie ET, Buisson A, Vivien D (2004) Neurotrophin-3-induced PI-3 kinase/Akt signaling rescues cortical neurons from apoptosis. Exp Neurol 187(1):38–46. doi:10.1016/j.expneurol.2004.01.002

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Kobayashi M, Matsuoka I (2000) Enhancement of sympathetic neuron survival by synergistic action of NT3 and GDNF. Neuroreport 11(11):2541–2545

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3(5):383–394. doi:10.1038/nrn812

    CAS  PubMed  Article  Google Scholar 

  203. 203.

    Funahashi Y, Namba T, Nakamuta S, Kaibuchi K (2014) Neuronal polarization in vivo: Growing in a complex environment. Curr Opin Neurobiol 27:215–223. doi:10.1016/j.conb.2014.04.009

    CAS  PubMed  Article  Google Scholar 

  204. 204.

    Okada N, Wada K, Goldsmith BA, Koizumi S (1996) SHP-2 is involved in neurotrophin signaling. Biochem Biophys Res Commun 229(2):607–611. doi:10.1006/bbrc.1996.1851

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    Easton JB, Royer AR, Middlemas DS (2006) The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. J Neurochem 97(3):834–845. doi:10.1111/j.1471-4159.2006.03789.x

    CAS  PubMed  Article  Google Scholar 

  206. 206.

    Goldsmith BA, Koizumi S (1997) Transient association of the phosphotyrosine phosphatase SHP-2 with TrkA is induced by nerve growth factor. J Neurochem 69(3):1014–1019

    CAS  PubMed  Article  Google Scholar 

  207. 207.

    Dance M, Montagner A, Salles JP, Yart A, Raynal P (2008) The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal 20(3):453–459. doi:10.1016/j.cellsig.2007.10.002

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Uren RT, Turnley AM (2014) Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player. Front Mol Neurosci 7:39. doi:10.3389/fnmol.2014.00039

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  209. 209.

    Arevalo JC, Yano H, Teng KK, Chao MV (2004) A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. EMBO J 23(12):2358–2368. doi:10.1038/sj.emboj.7600253

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Feng GS (2007) Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. Cell Res 17(1):37–41. doi:10.1038/sj.cr.7310140

    CAS  PubMed  Article  Google Scholar 

  211. 211.

    Shen Y, Inoue N, Heese K (2010) Neurotrophin-4 (ntf4) mediates neurogenesis in mouse embryonic neural stem cells through the inhibition of the signal transducer and activator of transcription-3 (stat3) and the modulation of the activity of protein kinase B. Cell Mol Neurobiol 30(6):909–916. doi:10.1007/s10571-010-9520-1

    CAS  PubMed  Article  Google Scholar 

  212. 212.

    Miranda C, Fumagalli T, Anania MC, Vizioli MG, Pagliardini S, Pierotti MA, Greco A (2010) Role of STAT3 in in vitro transformation triggered by TRK oncogenes. PLoS One 5(3), e9446. doi:10.1371/journal.pone.0009446

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  213. 213.

    Yamauchi J, Miyamoto Y, Tanoue A, Shooter EM, Chan JR (2005) Ras activation of a Rac1 exchange factor, Tiam1, mediates neurotrophin-3-induced Schwann cell migration. Proc Natl Acad Sci U S A 102(41):14889–14894. doi:10.1073/pnas.0507125102

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  214. 214.

    Yamauchi J, Chan JR, Miyamoto Y, Tsujimoto G, Shooter EM (2005) The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration. Proc Natl Acad Sci U S A 102(14):5198–5203. doi:10.1073/pnas.0501160102

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    Cherfils J (2014) GEFs and GAPs: mechanisms and structures. In: Ras superfamily small G proteins: biology and mechanisms 1. Springer, pp 51–63

  216. 216.

    Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93(1):269–309. doi:10.1152/physrev.00003.2012

    CAS  PubMed  Article  Google Scholar 

  217. 217.

    Yamauchi J, Chan JR, Shooter EM (2003) Neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase pathway. Proc Natl Acad Sci U S A 100(24):14421–14426. doi:10.1073/pnas.2336152100

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Newbern JM, Li X, Shoemaker SE et al (2011) Specific functions for ERK/MAPK signaling during PNS development. Neuron 69(1):91–105. doi:10.1016/j.neuron.2010.12.003

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. 219.

    Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA (2001) Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci 4(10):981–988. doi:10.1038/nn720

    CAS  PubMed  Article  Google Scholar 

  220. 220.

    Finegan KG, Wang X, Lee EJ, Robinson AC, Tournier C (2009) Regulation of neuronal survival by the extracellular signal-regulated protein kinase 5. Cell Death Differ 16(5):674–683. doi:10.1038/cdd.2008.193

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221.

    Morooka T, Nishida E (1998) Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells. J Biol Chem 273(38):24285–24288

    CAS  PubMed  Article  Google Scholar 

  222. 222.

    Vaudry D, Stork PJ, Lazarovici P, Eiden LE (2002) Signaling pathways for PC12 cell differentiation: making the right connections. Science 296(5573):1648–1649. doi:10.1126/science.1071552

    CAS  PubMed  Article  Google Scholar 

  223. 223.

    Li Y, Holtzman DM, Kromer LF, Kaplan DR, Chua-Couzens J, Clary DO, Knusel B, Mobley WC (1995) Regulation of TrkA and ChAT expression in developing rat basal forebrain: evidence that both exogenous and endogenous NGF regulate differentiation of cholinergic neurons. J Neurosci 15(4):2888–2905

    CAS  PubMed  Google Scholar 

  224. 224.

    Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6(8):603–614. doi:10.1038/nrn1726

    CAS  PubMed  Article  Google Scholar 

  225. 225.

    Nagappan G, Lu B (2005) Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Trends Neurosci 28(9):464–471. doi:10.1016/j.tins.2005.07.003

    CAS  PubMed  Article  Google Scholar 

  226. 226.

    Ortega JA, Alcantara S (2010) BDNF/MAPK/ERK-induced BMP7 expression in the developing cerebral cortex induces premature radial glia differentiation and impairs neuronal migration. Cereb Cortex 20(9):2132–2144. doi:10.1093/cercor/bhp275

    PubMed  Article  Google Scholar 

  227. 227.

    Cheng A, Coksaygan T, Tang H, Khatri R, Balice-Gordon RJ, Rao MS, Mattson MP (2007) Truncated tyrosine kinase B brain-derived neurotrophic factor receptor directs cortical neural stem cells to a glial cell fate by a novel signaling mechanism. J Neurochem 100(6):1515–1530. doi:10.1111/j.1471-4159.2006.04337.x

    CAS  PubMed  Google Scholar 

  228. 228.

    Alonso M, Medina JH, Pozzo-Miller L (2004) ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 11(2):172–178. doi:10.1101/lm.67804

    PubMed  PubMed Central  Article  Google Scholar 

  229. 229.

    Gottschalk WA, Jiang H, Tartaglia N, Feng L, Figurov A, Lu B (1999) Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Learn Mem 6(3):243–256

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, Lu B (2010) Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66(2):198–204. doi:10.1016/j.neuron.2010.03.035

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. 231.

    Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76(2):99–125. doi:10.1016/j.pneurobio.2005.06.003

    CAS  PubMed  Article  Google Scholar 

  232. 232.

    Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, Xia Z (2001) Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J Neurosci 21(2):434–443

    CAS  PubMed  Google Scholar 

  233. 233.

    Wang W, Pan YW, Zou J, Li T, Abel GM, Palmiter RD, Storm DR, Xia Z (2014) Genetic activation of ERK5 MAP kinase enhances adult neurogenesis and extends hippocampus-dependent long-term memory. J Neurosci 34(6):2130–2147. doi:10.1523/JNEUROSCI.3324-13.2014

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    Ohtsuka M, Fukumitsu H, Furukawa S (2009) Neurotrophin-3 stimulates neurogenetic proliferation via the extracellular signal-regulated kinase pathway. J Neurosci Res 87(2):301–306. doi:10.1002/jnr.21855

    CAS  PubMed  Article  Google Scholar 

  235. 235.

    Aletsee C, Beros A, Mullen L, Palacios S, Pak K, Dazert S, Ryan AF (2001) Ras/MEK but not p38 signaling mediates NT-3-induced neurite extension from spiral ganglion neurons. J Assoc Res Otolaryngol 2(4):377–387

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  236. 236.

    Ming G, Song H, Berninger B, Inagaki N, Tessier-Lavigne M, Poo M (1999) Phospholipase C-gamma and phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Neuron 23(1):139–148

    CAS  PubMed  Article  Google Scholar 

  237. 237.

    Yamashita T, Higuchi H, Tohyama M (2002) The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 157(4):565–570. doi:10.1083/jcb.200202010

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  238. 238.

    Yamashita T, Tohyama M (2003) The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat Neurosci 6(5):461–467. doi:10.1038/nn1045

    CAS  PubMed  Google Scholar 

  239. 239.

    Fujita Y, Yamashita T (2014) Axon growth inhibition by RhoA/ROCK in the central nervous system. Front Neurosci 8:338. doi:10.3389/fnins.2014.00338

    PubMed  PubMed Central  Article  Google Scholar 

  240. 240.

    Yamada M, Numakawa T, Koshimizu H, Tanabe K, Wada K, Koizumi S, Hatanaka H (2002) Distinct usages of phospholipase C gamma and Shc in intracellular signaling stimulated by neurotrophins. Brain Res 955(1-2):183–190

    CAS  PubMed  Article  Google Scholar 

  241. 241.

    Numakawa T, Kumamaru E, Adachi N, Yagasaki Y, Izumi A, Kunugi H (2009) Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma signaling for glutamate release via a glutamate transporter. Proc Natl Acad Sci U S A 106(2):647–652. doi:10.1073/pnas.0800888106

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  242. 242.

    Blanquet PR (2000) Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. Neuroscience 95(3):705–719

    CAS  PubMed  Article  Google Scholar 

  243. 243.

    Blum R, Konnerth A (2005) Neurotrophin-mediated rapid signaling in the central nervous system: mechanisms and functions. Physiology (Bethesda) 20:70–78. doi:10.1152/physiol.00042.2004

    CAS  Article  Google Scholar 

  244. 244.

    Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M (2002) Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36(1):121–137

    CAS  PubMed  Article  Google Scholar 

  245. 245.

    Mizoguchi Y, Ishibashi H, Nabekura J (2003) The action of BDNF on GABA(A) currents changes from potentiating to suppressing during maturation of rat hippocampal CA1 pyramidal neurons. J Physiol 548(Pt 3):703–709. doi:10.1113/jphysiol.2003.038935

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  246. 246.

    Canossa M, Gartner A, Campana G, Inagaki N, Thoenen H (2001) Regulated secretion of neurotrophins by metabotropic glutamate group I (mGluRI) and Trk receptor activation is mediated via phospholipase C signalling pathways. EMBO J 20(7):1640–1650. doi:10.1093/emboj/20.7.1640

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  247. 247.

    Yang F, He X, Feng L, Mizuno K, Liu XW, Russell J, Xiong WC, Lu B (2001) PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nat Neurosci 4(1):19–28. doi:10.1038/82858

    CAS  PubMed  Article  Google Scholar 

  248. 248.

    Lee FS, Chao MV (2001) Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc Natl Acad Sci U S A 98(6):3555–3560. doi:10.1073/pnas.061020198

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  249. 249.

    Lee FS, Rajagopal R, Chao MV (2002) Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors. Cytokine Growth Factor Rev 13(1):11–17

    CAS  PubMed  Article  Google Scholar 

  250. 250.

    Domeniconi M, Chao MV (2010) Transactivation of Trk receptors in spinal motor neurons. Histol Histopathol 25(9):1207–1213

    CAS  PubMed  Google Scholar 

  251. 251.

    Rajagopal R, Chen ZY, Lee FS, Chao MV (2004) Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. J Neurosci 24(30):6650–6658. doi:10.1523/JNEUROSCI.0010-04.2004

    CAS  PubMed  Article  Google Scholar 

  252. 252.

    Jeanneteau F, Chao MV (2006) Promoting neurotrophic effects by GPCR ligands. Novartis Found Symp 276:181–189, discussion 189–192, 233–187, 275–181

    CAS  PubMed  Article  Google Scholar 

  253. 253.

    Lee FS, Rajagopal R, Kim AH, Chang PC, Chao MV (2002) Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J Biol Chem 277(11):9096–9102. doi:10.1074/jbc.M107421200

    CAS  PubMed  Article  Google Scholar 

  254. 254.

    Wiese S, Jablonka S, Holtmann B, Orel N, Rajagopal R, Chao MV, Sendtner M (2007) Adenosine receptor A2A-R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB. Proc Natl Acad Sci U S A 104(43):17210–17215. doi:10.1073/pnas.0705267104

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  255. 255.

    Puehringer D, Orel N, Luningschror P, Subramanian N, Herrmann T, Chao MV, Sendtner M (2013) EGF transactivation of Trk receptors regulates the migration of newborn cortical neurons. Nat Neurosci 16(4):407–415. doi:10.1038/nn.3333

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  256. 256.

    Fenner BM (2012) Truncated TrkB: beyond a dominant negative receptor. Cytokine Growth Factor Rev 23(1-2):15–24. doi:10.1016/j.cytogfr.2012.01.002

    CAS  PubMed  Article  Google Scholar 

  257. 257.

    Li YX, Xu Y, Ju D, Lester HA, Davidson N, Schuman EM (1998) Expression of a dominant negative TrkB receptor, T1, reveals a requirement for presynaptic signaling in BDNF-induced synaptic potentiation in cultured hippocampal neurons. Proc Natl Acad Sci U S A 95(18):10884–10889

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  258. 258.

    Steinbeck JA, Methner A (2005) Translational downregulation of the noncatalytic growth factor receptor TrkB.T1 by ischemic preconditioning of primary neurons. Gene Expr 12(2):99–106

    PubMed  Article  Google Scholar 

  259. 259.

    Hartmann M, Brigadski T, Erdmann KS, Holtmann B, Sendtner M, Narz F, Lessmann V (2004) Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor. J Cell Sci 117(Pt 24):5803–5814. doi:10.1242/jcs.01511

    CAS  PubMed  Article  Google Scholar 

  260. 260.

    Eide FF, Vining ER, Eide BL, Zang K, Wang XY, Reichardt LF (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16(10):3123–3129

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261.

    Yacoubian TA, Lo DC (2000) Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat Neurosci 3(4):342–349. doi:10.1038/73911

    CAS  PubMed  Article  Google Scholar 

  262. 262.

    Brodeur GM, Minturn JE, Ho R et al (2009) Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 15(10):3244–3250. doi:10.1158/1078-0432.CCR-08-1815

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  263. 263.

    Carim-Todd L, Bath KG, Fulgenzi G et al (2009) Endogenous truncated TrkB.T1 receptor regulates neuronal complexity and TrkB kinase receptor function in vivo. J Neurosci 29(3):678–685. doi:10.1523/JNEUROSCI.5060-08.2009

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  264. 264.

    Ohira K, Funatsu N, Homma KJ, Sahara Y, Hayashi M, Kaneko T, Nakamura S (2007) Truncated TrkB-T1 regulates the morphology of neocortical layer I astrocytes in adult rat brain slices. Eur J Neurosci 25(2):406–416. doi:10.1111/j.1460-9568.2007.05282.x

    PubMed  Article  Google Scholar 

  265. 265.

    Ohira K, Kumanogoh H, Sahara Y, Homma KJ, Hirai H, Nakamura S, Hayashi M (2005) A truncated tropomyosin-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1. J Neurosci 25(6):1343–1353. doi:10.1523/JNEUROSCI.4436-04.2005

    CAS  PubMed  Article  Google Scholar 

  266. 266.

    Ohira K, Homma KJ, Hirai H, Nakamura S, Hayashi M (2006) TrkB-T1 regulates the RhoA signaling and actin cytoskeleton in glioma cells. Biochem Biophys Res Commun 342(3):867–874. doi:10.1016/j.bbrc.2006.02.033

    CAS  PubMed  Article  Google Scholar 

  267. 267.

    Fournier AE, Takizawa BT, Strittmatter SM (2003) Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci 23(4):1416–1423

    CAS  PubMed  Google Scholar 

  268. 268.

    Kozma R, Sarner S, Ahmed S, Lim L (1997) Rho family GTPases and neuronal growth cone remodelling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol Cell Biol 17(3):1201–1211

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  269. 269.

    Aroeira RI, Sebastiao AM, Valente CA (2015) BDNF, via truncated TrkB receptor, modulates GlyT1 and GlyT2 in astrocytes. Glia 63(12):2181–2197. doi:10.1002/glia.22884

    PubMed  Article  Google Scholar 

  270. 270.

    Michaelsen K, Zagrebelsky M, Berndt-Huch J, Polack M, Buschler A, Sendtner M, Korte M (2010) Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons. Eur J Neurosci 32(11):1854–1865. doi:10.1111/j.1460-9568.2010.07460.x

    CAS  PubMed  Article  Google Scholar 

  271. 271.

    Kryl D, Barker PA (2000) TTIP is a novel protein that interacts with the truncated T1 TrkB neurotrophin receptor. Biochem Biophys Res Commun 279(3):925–930. doi:10.1006/bbrc.2000.4058

    CAS  PubMed  Article  Google Scholar 

  272. 272.

    Palko ME, Coppola V, Tessarollo L (1999) Evidence for a role of truncated trkC receptor isoforms in mouse development. J Neurosci 19(2):775–782

    CAS  PubMed  Google Scholar 

  273. 273.

    Menn B, Timsit S, Calothy G, Lamballe F (1998) Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association. J Comp Neurol 401(1):47–64

    CAS  PubMed  Article  Google Scholar 

  274. 274.

    Esteban PF, Yoon HY, Becker J et al (2006) A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin. J Cell Biol 173(2):291–299. doi:10.1083/jcb.200512013

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  275. 275.

    Ibanez CF, Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35(7):431–440. doi:10.1016/j.tins.2012.03.007

    CAS  PubMed  Article  Google Scholar 

  276. 276.

    Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV (1991) High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350(6320):678–683. doi:10.1038/350678a0

    CAS  PubMed  Article  Google Scholar 

  277. 277.

    Esposito D, Patel P, Stephens RM, Perez P, Chao MV, Kaplan DR, Hempstead BL (2001) The cytoplasmic and transmembrane domains of the p75 and Trk A receptors regulate high affinity binding to nerve growth factor. J Biol Chem 276(35):32687–32695. doi:10.1074/jbc.M011674200

    CAS  PubMed  Article  Google Scholar 

  278. 278.

    Meeker R, Williams K (2014) Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol 9(5):615–628. doi:10.1007/s11481-014-9566-9

    PubMed  PubMed Central  Article  Google Scholar 

  279. 279.

    Gentry JJ, Rutkoski NJ, Burke TL, Carter BD (2004) A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF. J Biol Chem 279(16):16646–16656. doi:10.1074/jbc.M309209200

    CAS  PubMed  Article  Google Scholar 

  280. 280.

    Linggi MS, Burke TL, Williams BB, Harrington A, Kraemer R, Hempstead BL, Yoon SO, Carter BD (2005) Neurotrophin receptor interacting factor (NRIF) is an essential mediator of apoptotic signaling by the p75 neurotrophin receptor. J Biol Chem 280(14):13801–13808. doi:10.1074/jbc.M410435200

    CAS  PubMed  Article  Google Scholar 

  281. 281.

    Salehi AH, Xanthoudakis S, Barker PA (2002) NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway. J Biol Chem 277(50):48043–48050. doi:10.1074/jbc.M205324200

    CAS  PubMed  Article  Google Scholar 

  282. 282.

    Westwick JK, Bielawska AE, Dbaibo G, Hannun YA, Brenner DA (1995) Ceramide activates the stress-activated protein kinases. J Biol Chem 270(39):22689–22692

    CAS  PubMed  Article  Google Scholar 

  283. 283.

    Brann AB, Tcherpakov M, Williams IM, Futerman AH, Fainzilber M (2002) Nerve growth factor-induced p75-mediated death of cultured hippocampal neurons is age-dependent and transduced through ceramide generated by neutral sphingomyelinase. J Biol Chem 277(12):9812–9818. doi:10.1074/jbc.M109862200

    CAS  PubMed  Article  Google Scholar 

  284. 284.

    Hamanoue M, Middleton G, Wyatt S, Jaffray E, Hay RT, Davies AM (1999) p75-mediated NF-kappaB activation enhances the survival response of developing sensory neurons to nerve growth factor. Mol Cell Neurosci 14(1):28–40. doi:10.1006/mcne.1999.0770

    CAS  PubMed  Article  Google Scholar 

  285. 285.

    Khursigara G, Orlinick JR, Chao MV (1999) Association of the p75 neurotrophin receptor with TRAF6. J Biol Chem 274(5):2597–2600

    CAS  PubMed  Article  Google Scholar 

  286. 286.

    Carter BD, Kaltschmidt C, Kaltschmidt B, Offenhauser N, Bohm-Matthaei R, Baeuerle PA, Barde YA (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272(5261):542–545

    CAS  PubMed  Article  Google Scholar 

  287. 287.

    Khursigara G, Bertin J, Yano H, Moffett H, DiStefano PS, Chao MV (2001) A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2. J Neurosci 21(16):5854–5863

    CAS  PubMed  Google Scholar 

  288. 288.

    Lebrun-Julien F, Bertrand MJ, De Backer O, Stellwagen D, Morales CR, Di Polo A, Barker PA (2010) ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. Proc Natl Acad Sci U S A 107(8):3817–3822. doi:10.1073/pnas.0909276107

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  289. 289.

    Volosin M, Trotter C, Cragnolini A, Kenchappa RS, Light M, Hempstead BL, Carter BD, Friedman WJ (2008) Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via neurotrophin receptor-interacting factor in hippocampal neurons after seizures. J Neurosci 28(39):9870–9879. doi:10.1523/JNEUROSCI.2841-08.2008

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  290. 290.

    Kenchappa RS, Zampieri N, Chao MV, Barker PA, Teng HK, Hempstead BL, Carter BD (2006) Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons. Neuron 50(2):219–232. doi:10.1016/j.neuron.2006.03.011

    CAS  PubMed  Article  Google Scholar 

  291. 291.

    Geetha T, Kenchappa RS, Wooten MW, Carter BD (2005) TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor. EMBO J 24(22):3859–3868. doi:10.1038/sj.emboj.7600845

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  292. 292.

    Chen J, Wu X, Shao B, Zhao W, Shi W, Zhang S, Ni L, Shen A (2011) Increased expression of TNF receptor-associated factor 6 after rat traumatic brain injury. Cell Mol Neurobiol 31(2):269–275. doi:10.1007/s10571-010-9617-6

    PubMed  Article  CAS  Google Scholar 

  293. 293.

    Wu X, Xu XM (2016) RhoA/Rho kinase in spinal cord injury. Neural Regen Res 11(1):23–27. doi:10.4103/1673-5374.169601

    PubMed  PubMed Central  Article  Google Scholar 

  294. 294.

    Meeker RB, Williams KS (2015) The p75 neurotrophin receptor: at the crossroad of neural repair and death. Neural Regen Res 10(5):721–725. doi:10.4103/1673-5374.156967

    PubMed  PubMed Central  Article  Google Scholar 

  295. 295.

    Yamashita T, Tucker KL, Barde YA (1999) Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24(3):585–593. doi:10.1016/S0896-6273(00)81114-9

    CAS  PubMed  Article  Google Scholar 

  296. 296.

    Song W, Volosin M, Cragnolini AB, Hempstead BL, Friedman WJ (2010) ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J Neurosci 30(46):15608–15615. doi:10.1523/JNEUROSCI.2581-10.2010

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  297. 297.

    Sheng M, Sabatini BL, Sudhof TC (2012) Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol 4(5). doi:10.1101/cshperspect.a005777

  298. 298.

    Picconi B, Piccoli G, Calabresi P (2012) Synaptic dysfunction in Parkinson’s disease. Adv Exp Med Biol 970:553–572. doi:10.1007/978-3-7091-0932-8_24

    CAS  PubMed  Article  Google Scholar 

  299. 299.

    Sudhof TC, Rizo J (2011) Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol 3(12). doi:10.1101/cshperspect.a005637

  300. 300.

    Calabresi P, Mercuri NB, Di Filippo M (2009) Synaptic plasticity, dopamine and Parkinson’s disease: one step ahead. Brain 132(Pt 2):285–287. doi:10.1093/brain/awn340

    PubMed  Google Scholar 

  301. 301.

    Tancredi V, D’Arcangelo G, Mercanti D, Calissano P (1993) Nerve growth factor inhibits the expression of long-term potentiation in hippocampal slices. Neuroreport 4(2):147–150

    CAS  PubMed  Article  Google Scholar 

  302. 302.

    Brancucci A, Kuczewski N, Covaceuszach S, Cattaneo A, Domenici L (2004) Nerve growth factor favours long-term depression over long-term potentiation in layer II-III neurones of rat visual cortex. J Physiol 559(Pt 2):497–506. doi:10.1113/jphysiol.2004.068049

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  303. 303.

    Akaneya Y, Tsumoto T, Kinoshita S, Hatanaka H (1997) Brain-derived neurotrophic factor enhances long-term potentiation in rat visual cortex. J Neurosci 17(17):6707–6716

    CAS  PubMed  Google Scholar 

  304. 304.

    Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, Christie BR, Sejnowski TJ, Tuszynski MH (2009) NGF is essential for hippocampal plasticity and learning. J Neurosci 29(35):10883–10889. doi:10.1523/JNEUROSCI.2594-09.2009

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  305. 305.

    Arias ER, Valle-Leija P, Morales MA, Cifuentes F (2014) Differential contribution of BDNF and NGF to long-term potentiation in the superior cervical ganglion of the rat. Neuropharmacology 81:206–214. doi:10.1016/j.neuropharm.2014.02.001

    CAS  PubMed  Article  Google Scholar 

  306. 306.

    Edelmann E, Lessmann V, Brigadski T (2014) Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 76(Pt C):610–627. doi:10.1016/j.neuropharm.2013.05.043

    CAS  PubMed  Article  Google Scholar 

  307. 307.

    Lu B, Nagappan G, Lu Y (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 220:223–250. doi:10.1007/978-3-642-45106-5_9

    CAS  PubMed  Article  Google Scholar 

  308. 308.

    Patterson SL, Grover LM, Schwartzkroin PA, 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(6):1081–1088

    CAS  PubMed  Article  Google Scholar 

  309. 309.

    Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381(6584):706–709. doi:10.1038/381706a0

    CAS  PubMed  Article  Google Scholar 

  310. 310.

    Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92(19):8856–8860

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  311. 311.

    Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16(6):1137–1145

    CAS  PubMed  Article  Google Scholar 

  312. 312.

    Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8(8):1069–1077. doi:10.1038/nn1510

    CAS  PubMed  Article  Google Scholar 

  313. 313.

    Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, Barde YA (2008) Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 11(2):131–133. doi:10.1038/nn2038

    CAS  PubMed  Article  Google Scholar 

  314. 314.

    Bliss TV, Cooke SF (2011) Long-term potentiation and long-term depression: a clinical perspective. Clinics (Sao Paulo) 66(Suppl 1):3–17

    Article  Google Scholar 

  315. 315.

    Bliss TV, Collingridge GL, Morris RG (2014) Synaptic plasticity in health and disease: introduction and overview. Philos Trans R Soc Lond B Biol Sci 369 (1633):20130129. doi:10.1098/rstb.2013.0129

    Google Scholar 

  316. 316.

    Chen G, Kolbeck R, Barde YA, Bonhoeffer T, Kossel A (1999) Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation. J Neurosci 19(18):7983–7990

    CAS  PubMed  Google Scholar 

  317. 317.

    Ma L, Reis G, Parada LF, Schuman EM (1999) Neuronal NT-3 is not required for synaptic transmission or long-term potentiation in area CA1 of the adult rat hippocampus. Learn Mem 6(3):267–275

    CAS  PubMed  PubMed Central  Google Scholar 

  318. 318.

    Kaplan DR, Cooper E (2001) PI-3 kinase and IP3: partners in NT3-induced synaptic transmission. Nat Neurosci 4(1):5–7. doi:10.1038/82897

    CAS  PubMed  Article  Google Scholar 

  319. 319.

    Galvan EJ, Cosgrove KE, Barrionuevo G (2011) Multiple forms of long-term synaptic plasticity at hippocampal mossy fiber synapses on interneurons. Neuropharmacology 60(5):740–747. doi:10.1016/j.neuropharm.2010.11.008

    CAS  PubMed  Article  Google Scholar 

  320. 320.

    Ramos-Languren LE, Escobar ML (2013) Plasticity and metaplasticity of adult rat hippocampal mossy fibers induced by neurotrophin-3. Eur J Neurosci 37(8):1248–1259. doi:10.1111/ejn.12141

    CAS  PubMed  Article  Google Scholar 

  321. 321.

    Xie CW, Sayah D, Chen QS, Wei WZ, Smith D, Liu X (2000) Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4 gene. Proc Natl Acad Sci U S A 97(14):8116–8121. doi:10.1073/pnas.140204597

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  322. 322.

    Fan G, Egles C, Sun Y, Minichiello L, Renger JJ, Klein R, Liu G, Jaenisch R (2000) Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nat Neurosci 3(4):350–357. doi:10.1038/73921

    CAS  PubMed  Article  Google Scholar 

  323. 323.

    Zeng Y, Zhao D, Xie CW (2010) Neurotrophins enhance CaMKII activity and rescue amyloid-beta-induced deficits in hippocampal synaptic plasticity. J Alzheimers Dis 21(3):823–831. doi:10.3233/JAD-2010-100264

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  324. 324.

    Callaghan CK, Kelly AM (2013) Neurotrophins play differential roles in short and long-term recognition memory. Neurobiol Learn Mem 104:39–48. doi:10.1016/j.nlm.2013.04.011

    CAS  PubMed  Article  Google Scholar 

  325. 325.

    Wondolowski J, Dickman D (2013) Emerging links between homeostatic synaptic plasticity and neurological disease. Front Cell Neurosci 7:223. doi:10.3389/fncel.2013.00223

    PubMed  PubMed Central  Article  CAS  Google Scholar