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Increased expression of neurotrophins and their receptors in the mechanically compressed spinal cord of the spinal hyperostotic mouse (twy/twy)

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Abstract

The purpose of the present study was to identify any compensatory changes at the site of chronic compression of the spinal cord and neighboring segments. For this purpose, serial immunohistochemical and immunoblot analyses were performed for the expression levels of endogenous brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and their receptors, trkB and trkC in 24 tip-toe walking Yoshimura mice (twy/twy) aged 12–24 weeks. The twy mouse exhibits spontaneous calcified deposits posteriorly at the C1–C2 level, compressing the spinal cord. Immunoreactivities for BDNF, NT-3, trkB and trkC were preferentially localized in the gray matter, particularly in the anterior horn cells. In 24-week-old twy mice with severe compression, expression levels of these neurotrophins at the site of maximal compression were significantly lower than at the less- or non-compressed sites. In contrast, the expression levels of BDNF, NT-3, trkB and trkC were significantly higher at the rostral and caudal sites immediately adjacent to the maximal compression site. No such changes were noted in 12-week-old twy mice or in control Institute of Cancer Research mice. Our results suggest that overexpression of BDNF, NT-3, trkB and trkC in motoneuron areas neighboring the site of mechanical compression may represent compensatory changes in response to the compromised neuronal function at the level of compression, and that these proteins possibly contribute to neuronal survival and plasticity.

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References

  1. Al-Mefty O, Harkey HL, Marawi I (1993) Experimental chronic compressive myelopathy. J Neurosurg 79:550–561

    CAS  PubMed  Google Scholar 

  2. Arendt T, Brückner MK, Pagliusi S, Krell T (1995) Degeneration of rat cholinergic basal forebrain neurons and reactive changes in nerve growth factor expression after chronic neurotoxic injury. I. Degeneration and plastic response of basal forebrain neurons. Neuroscience 65:633–645

    CAS  PubMed  Google Scholar 

  3. Baba H, Maezawa Y, Imura S, Kawahara N, Nakahashi K, Tomita K (1996) Quantitative analysis of the spinal cord motoneuron under chronic compression: an experimental observation in the mouse. J Neurol 243:109–116

    CAS  PubMed  Google Scholar 

  4. Baba H, Uchida K, Maezawa Y, Furusawa N, Azuchi M, Imura S (1996) Lordotic alignment and posterior migration of the spinal cord following en bloc open-door laminoplasty for cervical myelopathy: a magnetic resonance imaging study. J Neurol 243:626–632

    CAS  PubMed  Google Scholar 

  5. Baba H, Maezawa Y, Uchida K, Furusawa N, Wada M, Imura S (1997) Plasticity of the spinal cord contributes to neurological improvement in patients treated by cervical decompressive surgery: a magnetic resonance imaging study. J Neurol 244:455–460

    Article  CAS  PubMed  Google Scholar 

  6. Baba H, Maezawa Y, Uchida K, Imura S, Kawahara N, Tomita K, Kudo M (1997) Three-dimensional topographic analysis of spinal accessory motoneurons under chronic mechanical compression: an experimental study in the mouse. J Neurol 244:222–229

    Article  CAS  PubMed  Google Scholar 

  7. Baba H, Uchida K, Sadato N, Yonekura Y, Kamoto Y, Maezawa Y, Furusawa N, Abe Y (1999) Potential usefulness of 18F-2-fluoro-deoxyd-glucose positron emission tomography in cervical compressive myelopathy. Spine 24:1449–1454

    Article  CAS  PubMed  Google Scholar 

  8. Barde YA (1994) Neurotrophins: a family of proteins supporting the survival of neurons. Prog Clin Biol Res 390:45–56

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Di Stefano PS, Friedman B, Radziejewski C, Alexander C, Boland P, Schick CM, Lindsay RM, Wiegand SJ (1992) The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons. Neuron 8:983–993

    PubMed  Google Scholar 

  11. Dougherty KD, Dreyfus CF, Black IB (2000) Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol Dis 7:574–585

    Article  CAS  PubMed  Google Scholar 

  12. El Shamy WM, Ernfos P (1996) A local action of neurotrophin-3 prevents the death of proliferating sensory neuron precursor cells. Neuron 16:963–972

    PubMed  Google Scholar 

  13. Ernfos P, Persson H (1991) Developmentally regulated expression of HDNF/NT-3 mRNA in rat spinal cord motoneurons and expression of BDNF mRNA in embryonic dorsal root ganglion. Eur J Neurosci 3:953–961

    PubMed  Google Scholar 

  14. Fehlings MG, Skaf G (1998) A review of the pathophysiology of cervical spondylotic myelopathy with insights for potential novel mechanisms drawn from traumatic spinal cord injury. Spine 23:2730–2736

    Article  CAS  PubMed  Google Scholar 

  15. Frisén J, Verge VM, Cullheim S, Persson H, Fried K, Middlemas DS, Hunter T, Hokfelt T, Risling M (1992) Increased levels of trkB mRNA and trkB protein-like immunoreactivity in the injured rat and cat spinal cord. Proc Natl Acad Sci USA 89:11282–11286

    CAS  PubMed  Google Scholar 

  16. Fukumitsu H, Furukawa Y, Tsusaka M, Kinukawa H, Nitta A, Nomoto H, Mima T, Furukawa S (1998) Simultaneous expression of brain-derived neurotropic factor and neurotrophin-3 in Cajal-Retzius, subplate and ventricular progenitor cells during early developmental stages of the rat cerebral cortex. Neuroscience 84:115–127

    Article  CAS  PubMed  Google Scholar 

  17. Funakoshi H, Frisen J, Barbany G, Timmusk T, Zachrisson O, Verge VM, Persson H (1993) Differential expression of mRNA for neurotrophins and their receptors after axonotomy of the sciatic nerve. J Cell Biol 123:455–465

    CAS  PubMed  Google Scholar 

  18. Hayashi M, Ueyama T, Nemoto K, Tamaki T, Senba E (2000) Sequential mRNA Expression for immediate early genes, cytokines, and neurotrophins in spinal cord injury. J Neurotrauma 17:203–218

    CAS  PubMed  Google Scholar 

  19. Henderson CE, Camu W, Mettling C, Gouin A, Poulsen K, Karihaloo M, Rullamas J, Evans T, McMahon SB, Armanini MP (1993) Neurotrophins promote motor neuron survival and are present in embryonic limb bud. Nature 363:266–270

    CAS  PubMed  Google Scholar 

  20. Houle JD, Ye JH (1999) Survival of chronically injured neurons can be prolonged by treatment with neurotrophic factors. Neuroscience 94:929–936

    CAS  PubMed  Google Scholar 

  21. Ikeda O, Murakami M, Ino H, Yamazaki M, Nemoto T, Koda M, Nakayama C, Moriya H (2001) Acute up-regulation of brain-derived neurotrophic factor expression resulting from experimentally induced injury in the rat spinal cord. Acta Neuropathol 102:239–245

    CAS  PubMed  Google Scholar 

  22. Johnson EM, Taniuchi M, DeStefano PS (1988) Expression and possible function of nerve growth factor receptors on Schwann cells. Trends Neurosci 11:299–304

    CAS  PubMed  Google Scholar 

  23. Kameyama T, Hashizume Y, Ando T, Takahashi A, Yanagi T, Mizuno J (1995) Spinal cord morphology and pathology in ossification of the posterior longitudinal ligament. Brain 118:263–278

    PubMed  Google Scholar 

  24. Kernie SG, Liebl DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19:1290–1300

    Article  CAS  PubMed  Google Scholar 

  25. 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 USA 92:9956–9960

    PubMed  Google Scholar 

  26. Leibl DJ, Huang W, Young W, Parada LF (2001) Regulation of trk receptors following contusion of the rat spinal cord. Exp Neurol 167:15–26

    Article  PubMed  Google Scholar 

  27. Lu B, Yokoyama M, Dreyfus CF, Black IB (1991) NGF gene expression in active growing brain glia. J Neurosci 11:318–326

    CAS  PubMed  Google Scholar 

  28. Maisonpierre PC, Belluscio L, Friedman B, Alderson RF, Wiegand SJ, Furth ME, Lindsay RM, Yancopoulos GD (1990) NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 5:501–509

    CAS  PubMed  Google Scholar 

  29. Martin D, Schoenen J, Delree P, Gilson V, Rogister B, Leprince P, Stevenaert A, Moonen G (1992) Experimental acute traumatic injury of adult rat spinal cord by a subdural inflatable balloon: methodology, behavioral analysis, and histopathology. J Neurosci Res 32:539–550

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL (1991) New protein fold revealed by a 2.3-Å resolution crystal structure of nerve growth factor. Nature 354:411–414

    Google Scholar 

  32. Merlio JP, Ernfors P, Kokaia Z, Middlemas DS, Bengzon J, Kokaia M, Smith ML, Siesjo BK, Hunter T, Lindvall O (1993) Increased production of trkB protein tyrosine kinase receptor after brain insults. Neuron 10:151–156

    CAS  PubMed  Google Scholar 

  33. Minichiello L, Korte M, Wolter D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Kein R (1999) Essential role for trkB receptors in hippocampus-mediated leaning. Neuron 24:401–414

    CAS  PubMed  Google Scholar 

  34. Mizuno J, Nakagawa H, Iwata K, Hashizume Y (1992) Pathology of spinal cord lesions caused by ossification of the posterior longitudinal ligament, with special reference to reversibility of the spinal cord lesion. Neurol Res 14:312–314

    CAS  PubMed  Google Scholar 

  35. Popovich PG, Stokes BT, Whitacre CC (1996) Concept of autoimmunity following spinal cord injury: possible roles for T lymphocytes in the traumatized central nervous system. J Neurosci Res 45:349–363

    Article  CAS  PubMed  Google Scholar 

  36. Schnell L, Schneider R, Kolbeck R, Barde Y-A, Schwab ME (1992) Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367:170–173

    Google Scholar 

  37. Sendtner M, Holtmann B, Kolbeck R, Thoenen H, Barde Y-A (1992) Brain-derived neurotropic factor prevents death of motoneurons in newborn rats after nerve section. Nature 360:757–759

    CAS  PubMed  Google Scholar 

  38. Snider WD (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627–638

    PubMed  Google Scholar 

  39. Taoka Y, Okajima K (1998) Spinal cord injury in the rat. Prog Neurobiol 56:341–358

    Article  CAS  PubMed  Google Scholar 

  40. Uchida K, Baba H, Maezawa Y, Furukawa S, Furusawa N, Imura S (1998) Histological investigation of spinal cord lesions in the spinal hyperostotic mouse (twy/twy): morphological changes in anterior horn cells and immunoreactivity to neurotropic factors. J Neurol 245:781–793

    Article  CAS  PubMed  Google Scholar 

  41. Uchida K, Baba H, Maezawa Y, Kubota C (2002) Progressive changes in neurofilament proteins and growth-associated protein-43 immunoreactivities at the site of cervical spinal cord compression in twy/twy mice. Spine 27:480–486

    Article  PubMed  Google Scholar 

  42. White FA, Silos-Santiago I, Molliver DC, Nishimura M, Phillips H, Barbacid M, Snider WD (1996) Synchronous onset of NGF and trkA survival dependence in developing dorsal root ganglia. J Neurosci 16:4662–4672

    CAS  PubMed  Google Scholar 

  43. Yamaura I, Yone K, Nakahara S, Nagamine T, Baba H, Uchida K, Komiya S (2002) Mechanism of destructive pathologic changes in the spinal cord under chronic mechanical compression. Spine 27:21–26

    Article  PubMed  Google Scholar 

  44. Yan Q, Elliott JL, Matheson C, Sun J, Zhang L, Mu X, Rex KL, Snider WD (1993) Influences of neurotrophins on mammalian motoneurons in vivo. J Neurobiol 24:1555–1577

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a grant from the Investigation Committee on Ossification of the Spinal Ligaments, the Public Health Bureau of the Ministry of Health and Welfare of the Japanese Government (1998–2000) and a Grant-in-Aid for General Scientific Research of the Ministry of Education, Science and Culture of Japan (grant no. 09671480).

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, School of Medicine, Fukui Medical University, Shimoaizuki 23, Matsuoka, 910-1193, Fukui, Japan

    Kenzo Uchida, Hisatoshi Baba, Yasuhisa Maezawa, Yasuo Kokubo, Chikara Kubota & Hideaki Nakajima

  2. Laboratory of Molecular Biology, Gifu Pharmaceutical University, Mitahora-higashi, 502-0002, Gifu, Japan

    Shoei Furukawa & Makoto Omiya

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  1. Kenzo Uchida
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  2. Hisatoshi Baba
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Correspondence to Kenzo Uchida.

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Uchida, K., Baba, H., Maezawa, Y. et al. Increased expression of neurotrophins and their receptors in the mechanically compressed spinal cord of the spinal hyperostotic mouse (twy/twy). Acta Neuropathol 106, 29–36 (2003). https://doi.org/10.1007/s00401-003-0691-4

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  • DOI: https://doi.org/10.1007/s00401-003-0691-4

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