Skip to main content
SpringerLink
Log in

Lack of TrkB and TrkC signaling alters the synaptogenesis and maturation of mossy fiber terminals in the hippocampus

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

We have studied the role of endogenous neurotrophins in the formation and maturation of intrinsic hippocampal connections in vivo and analyzed the dentate granule cell projections in both trkB(-/-) and trkC(-/-) mice. Immunohistochemistry against calbindin did not show major alterations in the distribution of granule cell axons, which were located exclusively in the hilus and the stratum lucidum. However, the thickness of the stratum lucidum (mossy fiber termination zone) and the density of mossy fiber terminals were reduced in the absence of TrkB signaling. Electron-microscopic analyses showed that the fine structure of mossy terminals was altered in both trkB(-/-) and trkC(-/-) mice. Mutant granule cell terminals were smaller than those in wild-type animals and showed a reduction in both the number of synaptic contacts and synaptic vesicles. Immunofluorescence assays demonstrated that the expression levels of most synaptic-associated proteins (v-SNAREs and t-SNAREs) were altered in the mossy fibers of trkB- and trkC-deficient mice. Our results therefore reveal that TrkB and TrkC signaling is required for the maturation of granule cell axons.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alcántara S, Frisén J, Del Río JA, Soriano E, Barbacid M, Silos-Santiago I (1997) TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death. J Neurosci 17:3623–3633

    Google Scholar 

  • Amaral DG, Dent J (1981) Development of the mossy fibers of the dentate gyrus. I. A light and electron microscopic study of mossy fibers and their expansions. J Comp Neurol 195:51–86

    Article  Google Scholar 

  • Baker RE, Dijkhuizen PA, Van Pelt J, Verhaagen J (1998) Growth of pyramidal, but not non-pyramidal, dendrites in long-term organotypic explants of neonatal rat neocortex chronically exposed to neurotrophin-3. Eur J Neurosci 10:1037–1044

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Barnstable CJ, Hofstein R, Akagawa K (1985) A marker for amacrine cell development in rat retina. Dev Brain Res 20:286–290

    Article  Google Scholar 

  • Brose N, Petrenko AG, Sudhof TC, Jahn R (1992) Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 256:1021–1025

    Google Scholar 

  • Cabelli RJ, Hohn A, Shatz T (1995) Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF. Science 267:1662–1666

    Google Scholar 

  • Cabelli RJ, Shelton DL, Segal RA, Shatz CJ (1997) Blockade of endogenous ligands of TrkB inhibits formation of ocular dominance columns. Neuron 19:63–76

    Article  Google Scholar 

  • Carmona MA, Martínez A, Soler A, Blasi J, Soriano E, Aguado F (2003) Ca2+-evoked synaptic transmission and neurotransmitter receptor levels are impaired in the forebrain of trkB(-/-) mice. Mol Cell Neurosci 22:210–226

    Article  Google Scholar 

  • Carter AR, Chen C, Schwartz PM, Segal RA (2002) Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure. J Neurosci 22:1316–1327

    Google Scholar 

  • Causing CG, Gloster A, Aloyz R, Bamji SX, Chang E, Fawcett J, Kuchel G, Miller FD (1997) Synaptic innervation density is regulated by neuron-derived BDNF. Neuron 18:257–267

    Article  Google Scholar 

  • Celio MR (1990) Calbindin D-28K and parvalbumin in the rat nervous system. Neuroscience 35:375–475

    Article  Google Scholar 

  • Collin C, Vicario-Abejon C, Rubio ME, Wenthold RJ, McKay RDG, Segal M (2001) Neurotrophins act at presynaptic terminals to active synapses among cultured hippocampal neurons. Eur J Neurosci 13:1273–1282

    Article  Google Scholar 

  • Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22:9754–9763

    Google Scholar 

  • Edelmann L, Hanson PI, Chapman ER, Jahn R (1995) Synaptobrevin binding to synaptophysin: a potential mechanism for controlling the exocytic fusion machine. EMBO J 14:1454–1466

    Google Scholar 

  • Ernfors P, Bengzon J, Kokaia Z, Persson H, Lindvall A (1991) Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron 7:165–176

    Article  Google Scholar 

  • Frotscher M, Drakew A, Heimrich B (2000) Role of afferent innervation and neuronal activity in dendritic development and spine maturation of fascia dentata granule cells. Cereb Cortex 10:946–951

    Article  Google Scholar 

  • Galuske RAW, Kim DS, Castren E, Thoenen H, Singer W (1996) Brain-derived neurotrophic factor reverses experience-dependent synaptic modifications in kitten visual cortex. Eur J Neurosci 8:1554–1559

    Google Scholar 

  • García E, McPherson P, Chilcote TJ, Takei K, De Camilli P (1995) rbSec1A and B colocalize with syntaxin 1 and SNAP-25 throughout the axon, but are not in a stable complex with syntaxin. J Cell Biol 129:105–120

    Article  Google Scholar 

  • Gottschalk W, Pozzo-Miller LD, Figurov A, Lu B (1998) Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J Neurosci 18:6830–6839

    Google Scholar 

  • Harris KM, Sultan P (1995) Variation in the number, location and size of synaptic vesicles provides an anatomical basis for the nonuniform probability of release at hippocampal CA1 synapsis. Neuropharmacology 43:1387–1395

    Google Scholar 

  • Henze DA, Urban NN, Barrionuevo G (2000) The multifarious hippocampal mossy fiber pathway: a review. Neuroscience 98:407–427

    Article  Google Scholar 

  • Horch HW, Kruttgen A, Portbury SD, Katz LC (1999) Destabilization of cortical dendrites and spines by BDNF. Neuron 23:353–364

    Article  Google Scholar 

  • Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736

    CAS  PubMed  Google Scholar 

  • Jin X, Hu H, Mathers PH, Agmon A (2003) Brain-derived neurotrophic factor mediates activity-dependent dendritic growth in nonpyramidal neocortical interneurons in developing organotypic cultures. J Neurosci 23:5662–5673

    Google Scholar 

  • Kang H, Schuman EM (1995) Long-lasting neurotrophin induced enhancement of synaptic transmission in the adult hippocampus. Science 267:1658–1662

    Google Scholar 

  • Klein R, Martin-Zanca D, Barbacid M, Parada LF (1990) Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system. Development 109:845–850

    Google Scholar 

  • Klein R, Smeyne RJ, Wurst W, Long LK, Auerbach BA, Joyner AL, Barbacid M (1993) Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75:113–122

    Article  Google Scholar 

  • Klein R, Silos-Santiago I, Smeyne RJ, Lira S, Brambilla S, Bryant S, Zhang L, Snider WD, Barbacid M (1994) Disruption of the neurotrophin receptor gene trkC eliminates muscle afferents and results in abnormal movements. Nature 368:249–251

    Article  Google Scholar 

  • Knipper M, Penha Berzaghi M da, Blochl A, Breer H, Thoenen H, Lindholm D (1994) Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci 6:668–671

    Google Scholar 

  • Kossel AH, Williams CV, Schweizer M, Kater SB (1997) Afferent innervation influences the development of dendritic branches and spines via both activity-dependent and non-activity-dependent mechanisms. J Neurosci 17:6314–6324

    Google Scholar 

  • Lauterborn JC, Isackson PJ, Gall CM (1994) Cellular localization of NGF and NT-3 mRNAs in postnatal rat forebrain. Mol Cell Neurosci 5:46–62

    Article  Google Scholar 

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

    Google Scholar 

  • Lin RC, Scheller RH (2000) Mechanisms of synaptic vesicle exocytosis. Annu Rev Cell Dev Biol 16:19–49

    Article  Google Scholar 

  • Loudes C, Petit F, Kordon C, Faivre-Bauman A (1999) Distinct populations of hypothalamic dopaminergic neurons exhibit differential responses to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). Eur J Neurosci 11:617–624

    Article  Google Scholar 

  • Lowenstein DH, Arsenault L (1996) Dentate granule cell layer collagen explant cultures: spontaneous axonal growth and induction by brain-derived neurotrophic factor or fibroblast growth factor. Neuroscience 74:1197–1208

    Google Scholar 

  • Martínez A, Alcántara S, Borrell V, Del Río JA, Blasi J, Otal R, Campos N, Boronat A, Barbacid M, Silos-Santiago I, Soriano E (1998) TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. J Neurosci 18:7336–7350

    Google Scholar 

  • Matteoli M, Takei K, Cameron R, Hurlbut P, Johnston PA, Sudhof TC, Jahn R, De Camilli P (1991) Association of Rab3a with synaptic vesicles at the late stages of the secretory pathway. J Cell Biol 115:625–633

    Article  Google Scholar 

  • McAllister AK, Katz LC, Lo DC (1997) Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth. Neuron 18:767–778

    Article  Google Scholar 

  • Minichiello L, Klein R (1996) TrkB and TrkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons. Genes Dev 10:2849–2858

    CAS  PubMed  Google Scholar 

  • Morfini G, DiTella MC, Feiguin F, Carri N, Cáceres A (1994) Neurotrophin-3 enhances neurite outgrowth in cultured hippocampal pyramidal neurons. J Neurosci Res 39:219–232

    Article  Google Scholar 

  • Paves H, Saarma M (1997) Neurotrophins as in vitro growth cone guidance molecules for embryonic sensory neurons. Cell Tissue Res 290:285–298

    Article  Google Scholar 

  • Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, Gopalakrishnan R, Oho C, Sheng ZH, Bai L (1999) Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 19:4972–4983

    Google Scholar 

  • Rico B, Xu B, Reichardt LF (2002) TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum. Nat Neurosci 5:225–233

    Article  Google Scholar 

  • Rosahl TW, Spillane D, Missler M, Herz J, Selig DK, Wolff JR, Hammer RE, Malenka RC, Sudhof TC (1995) Essential function of synapsins I and II in synaptic vesicle regulation. Nature 375:488–493

    CAS  PubMed  Google Scholar 

  • Sala R, Viegi A, Rossi FM, Pizzorusso T, Bonanno G, Raiteri M, Maffei L (1998) Nerve growth factor and brain-derived neurotrophic factor increase neurotransmitter release in the rat visual cortex. Eur J Neurosci 10:2185–2191

    Article  Google Scholar 

  • Scharfman HE (1997) Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. J Neurophysiol 78:1082–1095

    Google Scholar 

  • Scharfman HE, Goodman JH, Sollas AL (1999) Actions of brain-derived neurotrophic factor in slices from rats with spontaneous seizures and mossy fiber sprouting in the dentate gyrus. J Neurosci 19:5619–5631

    Google Scholar 

  • Schikorski T, Stevens CF (1997) Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci 17:5858–5867

    Google Scholar 

  • Schikorski T, Stevens CF (2001) Morphological correlates of functionally defined synaptic vesicle populations. Nat Neurosci 4:391–395

    Article  Google Scholar 

  • Schinder AF, Poo MM (2000) The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci 23:639–645

    Article  Google Scholar 

  • Shiff G, Morel N (1997) Association of syntaxin with SNAP-25 and VAMP (synaptobrevin) during axonal transport. J Neurosci Res 48:313–323

    Google Scholar 

  • Takei N, Sasaoka K, Inoue K, Takahashi M, Yasushisa E, Hatanaka H (1997) Brain-derived neurotrophic factor increases the stimulation-evoked release of glutamate and the levels of exocytosis-associated proteins in cultured cortical neurons from embryonic rats. J Neurochem 68:370–375

    Google Scholar 

  • Takei N, Numakawa T, Kozaki S, Sakai N, Yasushisa E, Takahashi M, Hatanaka H (1998) Brain-derived neurotrophic factor induces rapid and transient release of glutamate through the non-exocytotic pathway from cortical neurons. J Biol Chem 273:27620–27624

    Article  Google Scholar 

  • Tessarollo L, Tsoulfas P, Martin-Zanca D, Gilbert DJ, Jenkis NA, Copeland NG, Parada LF (1993) trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues. Development 118:463–475

    Google Scholar 

  • Tolwani RJ, Buckmaster PS, Varma S, Cosgaya JM, Wu Y, Suri C, Shooter EM (2002) BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus. Neuroscience 114:795–805

    Article  Google Scholar 

  • Tyler WJ, Pozzo-Miller LD (2001) BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci 21:4249–4258

    Google Scholar 

  • Wirth MJ, Brun A, Grabert J, Patz S, Wahle P (2003) Accelerated dendritic development of rat cortical pyramidal cells and interneurons after biolistic transfection with BDNF and NT4/5. Development 13:5827–5838

    Article  Google Scholar 

  • Xu B, Zang K, Ruff NL, Zhang YA, McConnell SK, Stryker MP, Reichardt LF (2000) Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB. Neuron 26:233–245

    Article  Google Scholar 

  • Yamada MK, Nakanishi K, Ohba S, Nakamura T, Ikegaya Y, Nishiyama N, Matsuki N (2002) Brain-derived neurotrophic factor promotes the maturation of GABAergic mechanisms in cultured hippocampal neurons. J Neurosci 22:7580–7585

    Google Scholar 

Download references

Acknowledgements

We thank Dr. J. Blasi for providing the various antibodies. We also thank Tanya Yates for editorial assistance. This study was supported by grants from the Comision Interministerial de Ciencia y Tecnología (SAF2001-3290) and the Marató de TV3 to Eduardo Soriano.

Author information

Authors and Affiliations

  1. Department of Cell Biology, Faculty of Biology, University of Barcelona and Barcelona Science Park, Barcelona, 08028, Spain

    Raquel Otal, Albert Martínez & Eduardo Soriano

  2. Neuronal Development and Regeneration Group (S1-A1), University of Barcelona and Barcelona Science Park, Josep Samitier 1-5, Barcelona, 08028, Spain

    Eduardo Soriano

Authors
  1. Raquel Otal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albert Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eduardo Soriano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eduardo Soriano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Otal, R., Martínez, A. & Soriano, E. Lack of TrkB and TrkC signaling alters the synaptogenesis and maturation of mossy fiber terminals in the hippocampus. Cell Tissue Res 319, 349–358 (2005). https://doi.org/10.1007/s00441-004-1020-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-004-1020-5

Keywords

Search

Navigation