Long-Term Development of Embryonic Cerebellar Grafts in Two Strains of Lurcher Mice

  • Jan Cendelin
  • Zdenka Purkartova
  • Jakub Kubik
  • Erik Ulbricht
  • Filip Tichanek
  • Yaroslav Kolinko
Original Paper

Abstract

For many degenerative cerebellar diseases, currently, no effective treatment that would substantially restore cerebellar functions is available. Neurotransplantation could be a promising therapy for such cases. Nevertheless, there are still severe limitations for routine clinical use. The aim of the work was to assess volume and morphology and functional impact on motor skills of an embryonic cerebellar graft injected in the form of cell suspension in Lurcher mutant and wild-type mice of the B6CBA and C3H strains after a 6-month survival period. The grafts survived in the majority of the mice. In both B6CBA and C3H Lurcher mice, most of the grafts were strictly delimited with no tendency to invade the host cerebellum, while in wild-type mice, graft-derived Purkinje cells colonized the host’s cerebellum. In C3H Lurcher mice, but not in B6CBA Lurchers, the grafts had smaller volume than in their wild-type counterparts. C3H wild-type mice had significantly larger grafts than B6CBA wild-type mice. No positive effect of the transplantation on performance in the rotarod test was observed. The findings suggest that the niche of the Lurcher mutant cerebellum has a negative impact on integration of grafted cells. This factor seems to be limiting for specific functional effects of the transplantation therapy in this mouse model of cerebellar degeneration.

Keywords

Cerebellum Cerebellar degeneration Lurcher mouse Purkinje cell Transplantation 

Notes

Acknowledgements

This publication was supported by the Charles University Grant Agency grant 716217, the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic, by the Charles University Research Fund (project number Q39) and student specific research project of the Charles University No. 260 394.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Manto MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum. 2005;4:2–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Mitoma H, Manto M. The physiological basis of therapies for cerebellar ataxias. Ther Adv Neurol Disord. 2016;9:396–413.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cendelin J. Experimental neurotransplantation treatment for hereditary cerebellar ataxias. Cerebellum Ataxias. 2016;3:7.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Cendelin J. Transplantation and stem cell therapy for cerebellar degenerations. Cerebellum. 2016;15:48–50.CrossRefPubMedGoogle Scholar
  5. 5.
    Cendelin J, Mitoma H, Manto M. Neurotransplantation therapy and cerebellar reserve. CNS Neurol Disord Drug Targets. 2017;  https://doi.org/10.2174/1871527316666170810114559.
  6. 6.
    Rossi F, Cattaneo E. Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci. 2002;3:401–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Li J, Imitola J, Snyder EY, Sidman RL. Neural stem cells rescue nervous Purkinje neurons by restoring molecular homeostasis of tissue plasminogen activator and downstream targets. J Neurosci. 2006;26:7839–48.CrossRefPubMedGoogle Scholar
  8. 8.
    Jones J, Jaramillo-Merchan J, Bueno C, Pastor D, Viso-Leon M, Martinez S. Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia. Neurobiol Dis. 2010;40:415–23.CrossRefPubMedGoogle Scholar
  9. 9.
    Lee H, Lee JK, Min WK, Bae JH, He X, Schuchman EH, et al. Bone marrow-derived mesenchymal stem cells prevent the loss of Niemann-pick type C mouse Purkinje neurons by correcting sphingolipid metabolism and increasing sphingosine-1-phosphate. Stem Cells. 2010;28:821–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Mendonca LS, Nobrega C, Hirai H, Kaspar BK, Pereira de Almeida L. Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice. Brain. 2015;138:320–35.CrossRefPubMedGoogle Scholar
  11. 11.
    Carletti B, Piemonte F, Rossi F. Neuroprotection: the emerging concept of restorative neural stem cell biology for the treatment of neurodegenerative diseases. Curr Neuropharmacol. 2011;9:313–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Phillips RJS. “Lurcher”, a new gene in linkage group XI of the house mouse. J Genet. 1960;57:35–42.CrossRefGoogle Scholar
  13. 13.
    Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N. Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature. 1997;388:769–73.CrossRefPubMedGoogle Scholar
  14. 14.
    Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, Mishina M. Selective expression of the glutamate receptor channel delta 2 subunit in cerebellar Purkinje cells. Biochem Biophys Res Commun. 1993;197:1267–76.CrossRefPubMedGoogle Scholar
  15. 15.
    Yuzaki M. The delta2 glutamate receptor: 10 years later. Neurosci Res. 2003;46:11–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Kashiwabuchi N, Ikeda K, Araki K, Hirano T, Shibuki K, Takayama C, et al. Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell. 1995;81:245–52.CrossRefPubMedGoogle Scholar
  17. 17.
    Kohda K, Kakegawa W, Matsuda S, Yamamoto T, Hirano H, Yuzaki M. The delta2 glutamate receptor gates long-term depression by coordinating interactions between two AMPA receptor phosphorylation sites. Proc Natl Acad Sci U S A. 2013;110:E948–57.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Caddy KW, Biscoe TJ. Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. Philos Trans R Soc Lond Ser B Biol Sci. 1979;287:167–201.CrossRefGoogle Scholar
  19. 19.
    Sultan F, Konig T, Mock M, Thier P. Quantitative organization of neurotransmitters in the deep cerebellar nuclei of the Lurcher mutant. J Comp Neurol. 2002;452:311–23.CrossRefPubMedGoogle Scholar
  20. 20.
    Zanjani SH, Selimi F, Vogel MW, Haeberle AM, Boeuf J, Mariani J, et al. Survival of interneurons and parallel fiber synapses in a cerebellar cortex deprived of Purkinje cells: studies in the double mutant mouse Grid2Lc/+;Bax(−/−). J Comp Neurol. 2006;497:622–35.CrossRefPubMedGoogle Scholar
  21. 21.
    Cendelin J, Tuma J, Korelusova I, Vozeh F. The effect of genetic background on behavioral manifestation of Grid2(Lc) mutation. Behav Brain Res. 2014;271:218–27.CrossRefPubMedGoogle Scholar
  22. 22.
    Coutelier M, Burglen L, Mundwiller E, Abada-Bendib M, Rodriguez D, Chantot-Bastaraud S, et al. GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia. Neurology. 2015;84:1751–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Dumesnil-Bousez N, Sotelo C. Partial reconstruction of the adult Lurcher cerebellar circuitry by neural grafting. Neuroscience. 1993;55:1–21.CrossRefPubMedGoogle Scholar
  24. 24.
    Heckroth JA, Hobart NJ, Summers D. Transplanted neurons alter the course of neurodegenerative disease in Lurcher mutant mice. Exp Neurol. 1998;154:336–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Cendelin J, Babuska V, Korelusova I, Houdek Z, Vozeh F. Long-term survival of solid embryonic cerebellar grafts in Lurcher mice. Neurosci Lett. 2012;515:23–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Babuska V, Houdek Z, Tuma J, Purkartova Z, Tumova J, Kralickova M, et al. Transplantation of embryonic cerebellar grafts improves gait parameters in ataxic Lurcher mice. Cerebellum. 2015;14:632–41.CrossRefPubMedGoogle Scholar
  27. 27.
    Cedikova M, Houdek Z, Babuska V, Kulda V, Vozeh F, Zech N, et al. Fate of two types of cerebellar graft in wild type and cerebellar mutant mice. J Appl Biomed. 2014;12:17–23.CrossRefGoogle Scholar
  28. 28.
    Cendelin J, Korelusova I, Vozeh F. Comparison of embryonic cerebellar graft survival in adult Lurcher mutant mice of strains C3H and C57Bl/7. Prague Med Rep. 2006;107:89–94.PubMedGoogle Scholar
  29. 29.
    Chang B, Hawes NL, Hurd RE, Davisson MT, Nusinowitz S, Heckenlively JR. Retinal degeneration mutants in the mouse. Vis Res. 2002;42:517–25.CrossRefPubMedGoogle Scholar
  30. 30.
    Howard V, Reed M. Unbiased stereology: three-dimensional measurement in microscopy. New York: Garland Science; 2004.Google Scholar
  31. 31.
    Mouton P. Unbiased stereology: a concise guide. Baltimore: JHU Press; 2011.Google Scholar
  32. 32.
    Gundersen HJ, Jensen EB, Kieu K, Nielsen J. The efficiency of systematic sampling in stereology—reconsidered. J Microsc. 1999;193:199–211.CrossRefPubMedGoogle Scholar
  33. 33.
    Ziegel J, Jensen EBV, Dorph-Petersen KA. Variance estimation for generalized Cavalieri estimators. Biometrika. 2011;98:187–98.CrossRefGoogle Scholar
  34. 34.
    Kolinko Y, Krakorova K, Cendelin J, Tonar Z, Kralickova M. Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes. Rev Neurosci. 2015;26:75–93.CrossRefPubMedGoogle Scholar
  35. 35.
    Kolinko Y, Cendelin J, Kralickova M, Tonar Z. Smaller absolute quantities but greater relative densities of microvessels are associated with cerebellar degeneration in Lurcher mice. Front Neuroanat. 2016;10:35.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing. Vienna; 2017. http://www.R-project.org/
  37. 37.
    Pekar S, Brabec M. Marginal models via GLS : a convenient yet neglected tool for the analysis of correlated data in the behavioural sciences. Ethology. 2016;122:621–31.CrossRefGoogle Scholar
  38. 38.
    Pinheiro J, Bates D, DebRoy S, Sarkar D, R Core Team. nlme: linear and nonlinear mixed effects models. 2014. https://cran.r -project.org/web/packages/nlme/index.html.
  39. 39.
    Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.Google Scholar
  40. 40.
    Sotelo C, Alvarado-Mallart RM. Reconstruction of the defective cerebellar circuitry in adult Purkinje cell degeneration mutant mice by Purkinje cell replacement through transplantation of solid embryonic implants. Neuroscience. 1987;20:1–22.CrossRefPubMedGoogle Scholar
  41. 41.
    Kohsaka S, Takayama H, Ueda T, Toya S, Tsukada Y. Reorganization of cerebellar cell suspension transplanted into the weaver mutant cerebellum and immunohistochemical detection of synaptic formation. Neurosci Res. 1988;6:162–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Triarhou LC, Low WC, Ghetti B. Intraparenchymal grafting of cerebellar cell suspensions to the deep cerebellar nuclei of pcd mutant mice, with particular emphasis on re-establishment of a Purkinje cell cortico-nuclear projection. Anat Embryol (Berl). 1992;185:409–20.CrossRefGoogle Scholar
  43. 43.
    Kaemmerer WF, Low WC. Cerebellar allografts survive and transiently alleviate ataxia in a transgenic model of spinocerebellar ataxia type-1. Exp Neurol. 1999;158:301–11.CrossRefPubMedGoogle Scholar
  44. 44.
    Purkartova Z, Tuma J, Pesta M, Kulda V, Hajkova L, Sebesta O, et al. Morphological analysis of embryonic cerebellar grafts in SCA2 mice. Neurosci Lett. 2014;558:154–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Sotelo C, Alvarado-Mallart RM. Embryonic and adult neurons interact to allow Purkinje cell replacement in mutant cerebellum. Nature. 1987;327:421–3.CrossRefPubMedGoogle Scholar
  46. 46.
    Carletti B, Grimaldi P, Magrassi L, Rossi F. Specification of cerebellar progenitors after heterotopic-heterochronic transplantation to the embryonic CNS in vivo and in vitro. J Neurosci. 2002;22:7132–46.PubMedGoogle Scholar
  47. 47.
    Leto K, Bartolini A, Yanagawa Y, Obata K, Magrassi L, Schilling K, et al. Laminar fate and phenotype specification of cerebellar GABAergic interneurons. J Neurosci. 2009;29:7079–91.CrossRefPubMedGoogle Scholar
  48. 48.
    Carletti B, Rossi F. Neurogenesis in the cerebellum. Neuroscientist. 2008;14:91–100.CrossRefPubMedGoogle Scholar
  49. 49.
    Leto K, Carletti B, Williams IM, Magrassi L, Rossi F. Different types of cerebellar GABAergic interneurons originate from a common pool of multipotent progenitor cells. J Neurosci. 2006;26:11682–94.CrossRefPubMedGoogle Scholar
  50. 50.
    Weimann JM, Johansson CB, Trejo A, Blau HM. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol. 2003;5:959–66.CrossRefPubMedGoogle Scholar
  51. 51.
    Duffin CA, McFarland R, Sarna JR, Vogel MW, Armstrong CL. Heat shock protein 25 expression and preferential Purkinje cell survival in the lurcher mutant mouse cerebellum. J Comp Neurol. 2010;518:1892–907.CrossRefPubMedGoogle Scholar
  52. 52.
    Cendelin J, Korelusova I, Vozeh F. A preliminary study of solid embryonic cerebellar graft survival in adult B6CBA Lurcher mutant and wild type mice. Anat Rec (Hoboken). 2009;292:1986–92.CrossRefGoogle Scholar
  53. 53.
    Carletti B, Williams IM, Leto K, Nakajima K, Magrassi L, Rossi F. Time constraints and positional cues in the developing cerebellum regulate Purkinje cell placement in the cortical architecture. Dev Biol. 2008;317:147–60.CrossRefPubMedGoogle Scholar
  54. 54.
    Carletti B, Rossi F. Selective rather than inductive mechanisms favour specific replacement of Purkinje cells by embryonic cerebellar cells transplanted to the cerebellum of adult Purkinje cell degeneration (pcd) mutant mice. Eur J Neurosci. 2005;22:1001–12.CrossRefPubMedGoogle Scholar
  55. 55.
    Cvetanovic M, Hu YS, Opal P. Mutant ataxin-1 inhibits neural progenitor cell proliferation in SCA1. Cerebellum. 2017;16:340–7.CrossRefPubMedGoogle Scholar
  56. 56.
    Vernet-der Garabedian B, Lemaigre-Dubreuil Y, Delhaye-Bouchaud N, Mariani J. Abnormal IL-1beta cytokine expression in the cerebellum of the ataxic mutant mice staggerer and lurcher. Brain Res Mol Brain Res. 1998;62:224–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Vogel MW, Fan H, Sydnor J, Guidetti P. Cytochrome oxidase activity is increased in +/Lc Purkinje cells destined to die. Neuroreport. 2001;12:3039–43.CrossRefPubMedGoogle Scholar
  58. 58.
    Garin N, Hornung JP, Escher G. Distribution of postsynaptic GABA(a) receptor aggregates in the deep cerebellar nuclei of normal and mutant mice. J Comp Neurol. 2002;447:210–7.CrossRefPubMedGoogle Scholar
  59. 59.
    McFarland R, Blokhin A, Sydnor J, Mariani J, Vogel MW. Oxidative stress, nitric oxide, and the mechanisms of cell death in Lurcher Purkinje cells. Dev Neurobiol. 2007;67:1032–46.CrossRefPubMedGoogle Scholar
  60. 60.
    Frederic F, Chautard T, Brochard R, Chianale C, Wollman E, Oliver C, et al. Enhanced endocrine response to novel environment stress and endotoxin in Lurcher mutant mice. Neuroendocrinology. 1997;66:341–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Kopmels B, Wollman EE, Guastavino JM, Delhaye-Bouchaud N, Fradelizi D, Mariani J. Interleukin-1 hyperproduction by in vitro activated peripheral macrophages from cerebellar mutant mice. J Neurochem. 1990;55:1980–5.CrossRefPubMedGoogle Scholar
  62. 62.
    Bakalian A, Kopmels B, Messer A, Fradelizi D, Delhaye-Bouchaud N, Wollman E, et al. Peripheral macrophage abnormalities in mutant mice with spinocerebellar degeneration. Res Immunol. 1992;143:129–39.CrossRefPubMedGoogle Scholar
  63. 63.
    Triarhou LC, Zhang W, Lee WH. Graft-induced restoration of function in hereditary cerebellar ataxia. Neuroreport. 1995;6:1827–32.CrossRefPubMedGoogle Scholar
  64. 64.
    Triarhou LC, Zhang W, Lee WH. Amelioration of the behavioral phenotype in genetically ataxic mice through bilateral intracerebellar grafting of fetal Purkinje cells. Cell Transplant. 1996;5:269–77.CrossRefPubMedGoogle Scholar
  65. 65.
    Fuca E, Guglielmotto M, Boda E, Rossi F, Leto K, Buffo A. Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice. Neurobiol Dis. 2017;102:49–59.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pathophysiology, Faculty of Medicine in PilsenCharles UniversityPlzenCzech Republic
  2. 2.Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPlzenCzech Republic
  3. 3.Department of Histology and Embryology, Faculty of Medicine in PilsenCharles UniversityPlzenCzech Republic
  4. 4.Laboratory of Quantitative Histology, Biomedical Center, Faculty of Medicine in PilsenCharles UniversityPlzenCzech Republic

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