Skip to main content
SpringerLink
Log in

Activity-induced and developmental downregulation of the Nogo receptor

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

Abstract.

The three axon growth inhibitory proteins, myelin associated glycoprotein, oligodendrocyte-myelin glycoprotein and Nogo-A, can all bind to the Nogo-66 receptor (NgR). This receptor is expressed by neurons with high amounts in regions of high plasticity where Nogo expression is also high. We hypothesized that simultaneous presence of high levels of Nogo and its receptor in neurons confers a locked state to hippocampal and cortical microcircuitry and that one or both of these proteins must be effectively and temporarily downregulated to permit plastic structural changes underlying formation of long-term memory. Hence, we subjected rats to kainic acid treatment and exposed rats to running wheels and measured NgR mRNA levels by quantitative in situ hybridization at different time points. We also studied spinal cord injuries and quantified NgR mRNA levels in spinal cord and ganglia during a critical postnatal period using real-time PCR. Strikingly, kainic acid led to a strong transient downregulation of NgR mRNA levels in gyrus dentatus, hippocampus, and neocortex during a time when BDNF mRNA was upregulated instead. Animals exposed to running wheels for 3 and 7, but not 1 or 21, days showed a significant downregulation of NgR mRNA in cortex, hippocampus and the dentate gyrus. NgR mRNA levels decreased from high to low expression in spinal cord and ganglia during the first week of life. No robust regulation of NgR was observed in the spinal cord following spinal cord injury. Together, our data show that NgR levels in developing and adult neurons are regulated in vivo under different conditions. Strong, rapid and transient downregulation of NgR mRNA in response to kainic acid and after wheel running in cortex and hippocampus suggests a role for NgR and Nogo-A in plasticity, learning and memory.

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. 1A–F.
Fig. 2A–D.
Fig. 3A–C.
Fig. 4A–F.
Fig. 5A–F.
Fig. 6A–D.

Similar content being viewed by others

References

  • Altman J, Bayer SA (1997) The development of the cerebellar system. CRC Press, Boca Raton

  • Ballarin M, Ernfors P, Lindefors N, Persson H (1991) Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain. Exp Neurol 114:35–43

    CAS  PubMed  Google Scholar 

  • Ben-Ari Y (1985) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403

    CAS  PubMed  Google Scholar 

  • Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M, Lindvall O (1997) Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A 94:10432–10437

    Article  CAS  PubMed  Google Scholar 

  • Caroni P, Schwab ME (1988) Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. J Cell Biol 106:1281–1288

    CAS  PubMed  Google Scholar 

  • Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403:434–439

    Article  CAS  PubMed  Google Scholar 

  • Cronin J, Dudek FE (1988) Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res 474:181–184

    CAS  PubMed  Google Scholar 

  • Dagerlind A, Friberg K, Bean AJ, Hökfelt T (1992) Sensitive mRNA detection using unfixed tissue: combined radioactive and non-radioactive in situ hybridization histochemistry. Histochemistry 98:39–49

    CAS  PubMed  Google Scholar 

  • David S, Aguayo AJ (1981) Axonal elongation into peripheral nervous system "bridges" after central nervous system injury in adult rats. Science 214:931–933

    CAS  PubMed  Google Scholar 

  • Davies SJ, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390:680–683

    CAS  PubMed  Google Scholar 

  • Davies SJ, Goucher DR, Doller C, Silver J (1999) Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci 19:5810–5822

    Google Scholar 

  • Domeniconi M, Cao Z, Spencer T, Sivasankaran R, Wang K, Nikulina E, Kimura N, Cai H, Deng K, Gao Y, He Z, Filbin M (2002) Myelin-associated glycoprotein interacts with the nogo66 receptor to inhibit neurite outgrowth. Neuron 35:283

    CAS  PubMed  Google Scholar 

  • Doroudi R, Gan LM, Selin Sjogren L, Jern S (2000) Effects of shear stress on eicosanoid gene expression and metabolite production in vascular endothelium as studied in a novel biomechanical perfusion model. Biochem Biophys Res Commun 269:257–264

    CAS  PubMed  Google Scholar 

  • Fournier AE, GrandPre T, Strittmatter SM (2001) Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409:341–346

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Pinilla F, van der Wal EA, Cotman CW (1995) Possible coordinated gene expressions for FGF receptor, FGF-5, and FGF-2 following seizures. Exp Neurol 133:164–174

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Pinilla F, Dao L, So V (1997) Physical exercise induces FGF-2 and its mRNA in the hippocampus. Brain Res 764:1–8

    CAS  PubMed  Google Scholar 

  • GrandPre T, Li S, Strittmatter SM (2002) Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417:547–551

    Article  CAS  PubMed  Google Scholar 

  • Gray WP, Sundstrom LE (1998) Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res 790:52–59

    Article  CAS  PubMed  Google Scholar 

  • Gruner JA (1992) A monitored contusion model of spinal cord injury in the rat. J Neurotrauma 9:123–128

    CAS  PubMed  Google Scholar 

  • Huber AB, Weinmann O, Brosamle C, Oertle T, Schwab ME (2002) Patterns of nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. J Neurosci 22:3553–3567

    CAS  PubMed  Google Scholar 

  • Humpel C, Wetmore C, Olson L (1993a) Regulation of brain-derived neurotrophic factor messenger RNA and protein at the cellular level in pentylenetetrazol-induced epileptic seizures. Neuroscience 53:909–918

    CAS  PubMed  Google Scholar 

  • Humpel C, Ebendal T, Cao Y, Olson L (1993b) Pentylenetetrazol seizures increase pro-nerve growth factor-like immunoreactivity in the reticular thalamic nucleus and nerve growth factor mRNA in the dentate gyrus. J Neurosci Res 35:419–427

    CAS  PubMed  Google Scholar 

  • Humpel C, Hoffer B, Stromberg I, Bektesh S, Collins F, Olson L (1994) Neurons of the hippocampal formation express glial cell line-derived neurotrophic factor messenger RNA in response to kainate-induced excitation. Neuroscience 59:791–795

    CAS  PubMed  Google Scholar 

  • Humpel C, Lindqvist E, Soderstrom S, Kylberg A, Ebendal T, Olson L (1995) Monitoring release of neurotrophic activity in the brains of awake rats. Science 269:552–554

    CAS  PubMed  Google Scholar 

  • Josephson A, Widenfalk J, Widmer HR, Olson L, Spenger C (2001) NOGO mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury. Exp Neurol 169:319–328

    Article  CAS  PubMed  Google Scholar 

  • Josephson A, Trifunovski A, Widmer HR, Widenfalk J, Olson L, Spenger C (2002) Nogo receptor gene activity: cellular localization and developmental regulation of mRNA in mice and humans. J Comp Neurol 453:292–304

    Article  CAS  PubMed  Google Scholar 

  • 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 341:149–152

    Google Scholar 

  • Liu BP, Fournier A, GrandPre T, Strittmatter SM (2002) Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 27:27

    Google Scholar 

  • Markakis EA, Gage FH (1999) Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol 406:449–460

    Article  CAS  PubMed  Google Scholar 

  • Martin KC, Kandel ER (1996) Cell adhesion molecules, CREB, and the formation of new synaptic connections. Neuron 17:567–570

    CAS  PubMed  Google Scholar 

  • McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE (1994) Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13:805–811

    CAS  PubMed  Google Scholar 

  • Merkler D, Metz GA, Raineteau O, Dietz V, Schwab ME, Fouad K (2001) Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. J Neurosci 21:3665–3673

    CAS  PubMed  Google Scholar 

  • Moreira EF, Jaworski CJ, Rodriguez IR (1999) Cloning of a novel member of the reticulon gene family (RTN3): gene structure and chromosomal localization to 11q13. Genomics 58:73–81

    Article  CAS  PubMed  Google Scholar 

  • Neeper SA, Gomez-Pinilla F, Choi J, Cotman C (1995) Exercise and brain neurotrophins. Nature 373:109

    CAS  PubMed  Google Scholar 

  • Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW (1996) Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 726:49–56

    CAS  PubMed  Google Scholar 

  • Niederost BP, Zimmermann DR, Schwab ME, Bandtlow CE (1999) Bovine CNS myelin contains neurite growth-inhibitory activity associated with chondroitin sulfate proteoglycans. J Neurosci 19:8979–8989

    CAS  PubMed  Google Scholar 

  • Olson L (1970) Fluorescence histochemical evidence for axonal growth and secretion from transplanted adrenal medullary tissue. Histochemie 22:1–7

    CAS  PubMed  Google Scholar 

  • Oudega M, Rosano C, Sadi D, Wood PM, Schwab ME, Hagg T (2000) Neutralizing antibodies against neurite growth inhibitor NI-35/250 do not promote regeneration of sensory axons in the adult rat spinal cord. Neuroscience 100:873–883

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain. Academic, San Diego, CA

  • Paxinos G, Ashwell KS, Törk I (1994) Atlas of the developing rat nervous system. Academic, San Diego, CA

  • Schwab ME, Caroni P (1988) Oligodendrocytes and CNS myelin are nonpermissive substrates for neurite growth and fibroblast spreading in vitro. J Neurosci 8:2381–2393

    CAS  PubMed  Google Scholar 

  • Schwab ME, Thoenen H (1985) Dissociated neurons regenerate into sciatic but not optic nerve explants in culture irrespective of neurotrophic factors. J Neurosci 5:2415–2423

    CAS  PubMed  Google Scholar 

  • Shyu BC, Andersson SA, Thoren P (1984) Spontaneous running in wheels. A microprocessor assisted method for measuring physiological parameters during exercise in rodents. Acta Physiol Scand 121:103–109

    CAS  PubMed  Google Scholar 

  • Tauck DL, Nadler JV (1985) Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci 5:1016–1022

    CAS  PubMed  Google Scholar 

  • Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M, Persson H (1993) Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10:475–489

    CAS  PubMed  Google Scholar 

  • van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 96:13427–13431

    Article  PubMed  Google Scholar 

  • Wang JY, Miller SJ, Falls DL (2000) The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain. J Biol Chem 26:2841–2851

    Google Scholar 

  • Wang KC, Koprivica V, Kim JA, Sivasankaran R, Guo Y, Neve RL, He Z (2002a) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941–944

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Chun SJ, Treloar H, Vartanian T, Greer CA, Strittmatter SM (2002b) Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. J Neurosci 22:5505–5515

    CAS  PubMed  Google Scholar 

  • Wang KC, Kim JA, Sivasankaran, R, Segal R, He Z (2002c) p75 interacts with Nogo receptor as a co-receptor for Nogo, MAG and Omgp. Nature 420:74–78

    Article  CAS  PubMed  Google Scholar 

  • Wetmore C, Olson L, Bean AJ (1994) Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors. J Neurosci 14:1688–1700

    CAS  PubMed  Google Scholar 

  • Widenfalk J, Olson L, Thoren P (1999) Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain. Neurosci Res 34:125–132

    Article  CAS  PubMed  Google Scholar 

  • Widenfalk J, Lundstromer K, Jubran M, Brene S, Olson L (2001) Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid. J Neurosci 21:3457–3475

    CAS  PubMed  Google Scholar 

  • Woolf CJ, Bloechlinger S (2002) Neuroscience: enhanced: it takes more than two to Nogo. Science 297:1132–1134

    Article  CAS  PubMed  Google Scholar 

  • Zafra F, Hengerer B, Leibrock J, Thoenen H, Lindholm D (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 9:3545–3550

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements.

We thank Karin Pernold, Karin Lundströmer and Eva Lindqvist for excellent technical assistance and Ida Engqvist for editing the manuscript.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Karolinska Institutet, 17177, Stockholm, Sweden

    Anna Josephson, Alexandra Trifunovski, Johan Widenfalk, Stefan Brené, Lars Olson & Christian Spenger

  2. Center for Genomics and Bioinformatics, Karolinska Institutet, 17177, Stockholm, Sweden

    Camilla Schéele & Claes Wahlestedt

  3. Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, Retzius väg 8, 171 77, Sweden

    Christian Spenger

Authors
  1. Anna Josephson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandra Trifunovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Camilla Schéele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johan Widenfalk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claes Wahlestedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stefan Brené
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lars Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christian Spenger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Spenger.

Additional information

The first two authors contributed equally to this article. The study was supported by grants from the Swedish Research Council, PHS, AMF, NIDa, the Petrus and Augusta Hedlunds stiftelse and the A. and J. Mattsons Minnesstiftelse för sonen Johan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Josephson, A., Trifunovski, A., Schéele, C. et al. Activity-induced and developmental downregulation of the Nogo receptor. Cell Tissue Res 311, 333–342 (2003). https://doi.org/10.1007/s00441-002-0695-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-002-0695-8

Keywords

Search

Navigation