Transplantation in Huntington’s Disease: Experimental Basis and Clinical Perspectives

  • A. Björklund
  • K. Wictorin
Part of the Basic and Clinical Aspects of Neuroscience book series (BASIC, volume 5)


Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease in the pathogenesis of which a locus on chromosome 4 is thought to play an as yet undetermined role. Atrophy of the striatum, associated with extensive neuronal loss, is the most constant neuropathologic finding, and the extent of striatal atrophy has been correlated with the progression of the disease [21]. Affected patients, in whom the disease usually develops at 35–45 years of age, show a series of symptoms including severe cognitive and emotional disturbances and incapacitating involuntary movements (chorea). The disease generally progresses over 10–20 years, leading directly or indirectly to death (for comprehensive reviews, see [2] and [12]).


Globus Pallidus Kainic Acid Ibotenic Acid Striatal Lesion Glutamic Acid Decarboxylase Activity 
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  1. 1.
    Bregman B, Reier PJ (1986) Neural tissue transplants rescue axo- tomized rubrospinal cells from retrograde death. J Comp Neurol 244: 86–95PubMedCrossRefGoogle Scholar
  2. 2.
    Bruyn GW (1968) Huntington’s chorea, historical, clinical and laboratory synopsis. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol 6, pp 298–378, North-Holland Publ., AmsterdamGoogle Scholar
  3. 3.
    Campbell K, Kalen P, Wictorin K, Lundberg C, Mandel RM, Björklund A (1993) Characterization of GAB A release from intrastriatal striatal transplants: dependence on host-derived afferents. Neuroscience (in press)Google Scholar
  4. 4.
    Clarke DJ, Dunnett SB, Isacson O, Sirinathsinghji DJS, Björklund A (1988) Striatal grafts in rats with unilateral neostriatal lesions: I. Ultrastructural evidence of afferent synaptic inputs from the host nigrostriatal pathway. Neuroscience 24: 791–801PubMedCrossRefGoogle Scholar
  5. 5.
    Coyle JT, Schwartz R (1976) Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature 263: 244–246PubMedCrossRefGoogle Scholar
  6. 6.
    Deckel AW, Robinson RG, Coyle JT, Sanberg PR (1983) Reversal of longterm locomotor abnormalities in the kainic acid model of Huntington’s disease by day 18 fetal striatal implants. Eur J Pharmacol 93: 287–288PubMedCrossRefGoogle Scholar
  7. 7.
    Deckel AW, Moran TH, Coyle JT, Sanberg PR, Robinson RG (1986) Anatomical predictors of behavioral recovery following striatal transplants. Brain Res 365: 249–258PubMedCrossRefGoogle Scholar
  8. 8.
    Dunnett SB, Iversen SD (1981) Learning impairments following selective kainic acid-induced lesions within the neostriatum of rats. Behav Brain Res 2: 189–209PubMedCrossRefGoogle Scholar
  9. 9.
    Dunnett SB, Isacson O, Sirinathsinghji DJS, Clarke DJ, Björklund A (1988) Striatal grafts in rats with unilateral neostriatal lesions: recovery from dopamine dependent asymmetry and deficits in skilled paw reaching. Neuroscience 24: 813–820PubMedCrossRefGoogle Scholar
  10. 10.
    Graybiel AM, Liu FC, Dunnett SB (1989) Intrastriatal grafts derived from fetal striatal primordia: I. Phenotopy and modular organization. J Neurosci 9: 3250–3271PubMedGoogle Scholar
  11. 11.
    Hantraye P, Riche D, Maziere M, Isacson O (1990) An experimental primate model for Huntington’s disease: anatomical and behavioural studies of unilateral excitotoxic lesions of the caudate- putamen in the baboon. Exp Neurol 108: 91–104PubMedCrossRefGoogle Scholar
  12. 12.
    Harper PS (ed) (1991) Huntington’s disease. Major problems in neurology, vol 22. Saunders, LondonGoogle Scholar
  13. 13.
    Hoffer BJ, Olson L (1991) Ethical issues in brain-cell transplantation. Trends Neurosci 14: 415–418CrossRefGoogle Scholar
  14. 14.
    Isacson O, Brundin P, Kelly PAT, Gage FH, Björklund A (1984) Functional neuronal replacement by grafted neurons in the ibotenic acid-lesioned striatum. Nature 311: 458–460PubMedCrossRefGoogle Scholar
  15. 15.
    Isacson O, Brundin P, Gage FH, Björklund A (1985) Neural grafting in a rat model of Huntington’s disease. Progressive neurochemical changes after neostriatal ibotenate lesions and striatal tissue grafting. Neuroscience 16: 799–817PubMedCrossRefGoogle Scholar
  16. 16.
    Isacson O, Dunnett SB, Björklund A (1986) Graft-induced behavioural recovery in an animal model of Huntington’s disease. Proc Natl Acad Sci USA 83: 2728–2732PubMedCrossRefGoogle Scholar
  17. 17.
    Isacson O, Dawbarn D, Brundin P, Gage FH, Emson PC, Björklund A (1987) Neural grafting in a rat model of Huntington’s disease: striosomal-like organization of striatal grafts as revealed by immunocytochemistry and receptor autoradiography. Neuroscience 22:481–4197PubMedCrossRefGoogle Scholar
  18. 18.
    Isacson O, Riche D, Hantraye P, Sofroniew MV, Maziere M (1989) A primate model of Huntington’s disease: cross-species implantation of striatal precursor cells to the excitotoxically lesioned baboon caudate-putamen. Exp Brain Res 75: 213–220PubMedCrossRefGoogle Scholar
  19. 19.
    Isacson O, Hantraye P, Riche D, Schumacher JM, Maziere M (1991) The relationship between symptoms and functional anatomy in the chronic neurodegenerative diseases: from pharmacological to biological replacement therapy in Huntington’s disease. In: Lindvall O, Björklund O, Widner H (eds) Intracerebral transplantation in movement disorders. Elsevier, Amsterdam, pp 245–258Google Scholar
  20. 20.
    Kesslak JP, Nieto-Sampedro M, Globus J, Cotman CW (1986) Transplants of purified astrocytes promote behavioral recovery after frontal cortex ablation. Exp Neurol 92: 377–390PubMedCrossRefGoogle Scholar
  21. 21.
    Kuhl DE, Phelps ME, Markham C, Winter J, Metter J, Riege W (1982) Cerebral metabolism and atrophy in Huntington’s disease determined by 18FDG and computed tomographic scan. Ann Neurol 12: 425–434PubMedCrossRefGoogle Scholar
  22. 22.
    Labandeira-Garcia JL, Wictorin K, Cunningham Jr ET, Björklund A (1991) Development of intrastriatal striatal grafts and their afferent innervation from the host. Neuroscience 42: 407–426PubMedCrossRefGoogle Scholar
  23. 23.
    Lindvall O (1989) Transplantation into the human brain: present status and future possibilities. J Neurol Neurosurg Psychiatry [Suppi]: 39–54Google Scholar
  24. 24.
    Lindvall O (1991) Prospect of transplantation in human neuro-degenerative diseases. Trends Neurosci 14: 376–384PubMedCrossRefGoogle Scholar
  25. 25.
    Liu F-C, Graybiel AM, Dunnett SB, Baughman RW (1990) Intrastriatal grafts derived from fetal striatal primordia: II. Compartmental alignment of cholinergic and dopaminergic systems. J Comp Neurol 295: 1–15PubMedCrossRefGoogle Scholar
  26. 26.
    Liu FC, Dunnett SB, Robertson HA, Graybiel AM (1991) Intrastriatal grafts derived from fetal striatal primordia: III. Introduction of modular patterns of Fos-like immunoreactivity by cocaine. Exp Brain Res 85: 501–506PubMedCrossRefGoogle Scholar
  27. 27.
    Mandel RJ, Wictorin K, Cenci MA, Björklund A (1992) Fos expression in intrastriatal grafts: regulation by host dopaminergic afferents. Brain Res 583: 207–215PubMedCrossRefGoogle Scholar
  28. 28.
    McGeer EG, McGeer PL (1976) Duplication of biochemical changes of Huntington’s chorea by intrastriatal injection of glutamic and kainic acids. Nature 263: 517–519PubMedCrossRefGoogle Scholar
  29. 29.
    Mogenson GJ, Nielsen MA (1983) Evidence that an accumbens to subpallidal GABAergic projection contributes to locomotor activity. Brain Res Bull 11: 309–314PubMedCrossRefGoogle Scholar
  30. 30.
    Norman AB, Giordano M, Sanberg PR (1989) Fetal striatal tissue grafts into excitotoxin-lesioned striatum: pharmacological and behavioural aspects. Pharmacol Biochem Behav 34: 139–147PubMedCrossRefGoogle Scholar
  31. 31.
    Pisa M, Sanberg PR, Fibiger HC (1981) Striatal injections of kainic acid selectively impair serial memory performance in the rat. Exp Neurol 74: 633–653PubMedCrossRefGoogle Scholar
  32. 32.
    Pritzel M, Isacson O, Brundin P, Wiklund L, Björklund A (1986) Afferent and efferent connections of striatal grafts implanted into the ibotenic acid lesioned neostriatum in adult rats. Exp Brain Res 65: 112–126PubMedCrossRefGoogle Scholar
  33. 33.
    Rutherford A, Garcia-Munoz M, Dunnett SB, Arbuthnott GW (1987) Electrophysiological demonstration of host cortical inputs to striatal grafts. Neurosci Lett 83: 275–281PubMedCrossRefGoogle Scholar
  34. 34.
    Saji M, Reis DJ (1987) Delayed transneuronal death of substantia nigra neurons prevented by gammaaminobutyric acid agonist. Science 235: 66–69PubMedCrossRefGoogle Scholar
  35. 35.
    Sanberg PR, Fibiger HC (1979) Body weight, feeding and drinking behaviors in rats with kainic acid lesions of the striatal neurons: with a note on body weight smyptomatology in Huntington’s disease. Exp Neurol 66: 444–466PubMedCrossRefGoogle Scholar
  36. 36.
    Sanberg PR, Henault MA, Deckel AW (1986) Locomotor hyper-activity: effects of multiple striatal transplants in an animal model of Huntington’s disease. Pharmacol Biochem Behav 25 [Suppl]: 297–301PubMedCrossRefGoogle Scholar
  37. 37.
    Sanberg PR, Giordano M, Henault MA, Nash DR, Ragozzino ME, Hagenmayer-Houser SH (1989) Intraparenchymal striatal transplants required for maintenance of behavioural recovery in an animal model of Huntington’s disease. J Neural Transpl 1: 23–31CrossRefGoogle Scholar
  38. 38.
    Schumacher JM, Short MP, Hyman BT, Breakefield XO, Isacson O (1991) Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids. Neuroscience 45: 561–570PubMedCrossRefGoogle Scholar
  39. 39.
    Schwartz R, Hôkfelt T, Fuxe K, Jonsson G, Goldstein M, Terenius L (1979) Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study. Exp Brain Res 37: 199–216Google Scholar
  40. 40.
    Sievers J, Hausmann B, Berry M (1989) Fetal brain grafts rescue adult retinal ganglion cells from axotomy-induced cell death. J Comp Neurol 281: 467–478PubMedCrossRefGoogle Scholar
  41. 41.
    Sirinathsinghji DJS, Dunnett SB, Isacson O, Clarke DJ, Kendrick K, Björklund A (1988) Striatal grafts in rats with unilateral neostriatal lesions: II. In vivo monitoring of GABA release in globus pallidus and substantia nigra. Neuroscience 24: 803–811PubMedCrossRefGoogle Scholar
  42. 42.
    Sirinathsinghji DJS, Morris BJ, Wisden W, Northrop A, Hunt SP, Dunnett SB (1990) Gene expression in striatal grafts: I. Cellular localization of neurotransmitter mRNAs. Neuroscience 34: 675–686PubMedCrossRefGoogle Scholar
  43. 43.
    Sofroniew MV, Isacson O, Björklund A (1986) Cortical grafts prevent atrophy of cholinergic basal nucleus neurons induced by excitotoxic cortical damage. Brain Res 378: 409–415PubMedCrossRefGoogle Scholar
  44. 44.
    Sokoloff L (1977) Relation between physiological function and energy metabolism in the central nervous system. J Neurochem 29: 13–26PubMedCrossRefGoogle Scholar
  45. 45.
    Tulipan N, Huang S, Whetsell WO, Allen GS (1986) Neonatal striatal grafts prevent lethal syndrome produced by bilateral intrastriatal injection of kainic acid. Brain Res 377: 163–167PubMedCrossRefGoogle Scholar
  46. 46.
    Wictorin K, Isacson O, Fischer W, Nithias FH, Peschanski M, Björklund A (1988) Connectivity of striatal grafts implanted into the ibotenic acid lesioned striatum: I. Subcortical afferents. Neuroscience 27: 547–562PubMedCrossRefGoogle Scholar
  47. 47.
    Wictorin K, Björklund A (1989) Connectivity of striatal grafts implanted into the ibotenic acid lesioned striatum: II. Cortical afferents. Neuroscience 30: 297–311PubMedCrossRefGoogle Scholar
  48. 48.
    Wictorin K, Clarke DJ, Bolam JP, Björklund A (1989) Host corticostriatal fibres establish synaptic connections with grafts striatal neurons in the ibotenic acid lesioned striatum. Eur J Neurosci 1: 189–195PubMedCrossRefGoogle Scholar
  49. 49.
    Wictorin K, Ouimet CC, Björklund A (1989) Intrinsic organization and connectivity of intrastriatal striatal transplants in rats as revealed by DARPP-32 immunohistochemistry: specificity of connections with the lesioned host brain. Eur J Neurosci 1: 690–701PubMedCrossRefGoogle Scholar
  50. 50.
    Wictorin K, Simerly RB, Isacson O, Swanson LW, Björklund A (1989) Connectivity of striatal grafts implanted into the ibotenic acid lesioned striatum: III. Efferent projecting graft neurons and their relation to host afferents with the grafts. Neuroscience 30: 313–330PubMedCrossRefGoogle Scholar
  51. 51.
    Wictorin K, Clarke DJ, Bolam JP, Björklund A (1990) Fetal striatal neurons grafted into the ibotenate lesioned striatum: efferent projections and synaptic contacts in the host globus pallidus. Neuroscience 37: 301–315PubMedCrossRefGoogle Scholar
  52. 52.
    Wictorin K, Lagenaur CF, Lund RD, Björklund A (1991) Efferent projections to the host brain from intrastriatal striatal mouse-to-rat grafts: time-course and tissue-type specificity as revealed by a mouse specific neuronal marker. Eur J Neurosci 3: 86–101PubMedCrossRefGoogle Scholar
  53. 53.
    Xu ZC, Wilson CJ, Emson PC (1989) Restoration of the corticostriatal projection in rat neostriatal grafts: electron microscopic analysis. Neuroscience 29: 539–550PubMedCrossRefGoogle Scholar
  54. 54.
    Xu ZC, Wilson CJ, Emson PC (1990) Restoration of thalamostriatal projections in rat neostriatal grafts: an electron microscopic analysis. J Comp Neurol 303: 2–14Google Scholar
  55. 55.
    Xu ZC, Wilson CJ, Emson PC (1991) Synaptic potentials evoked in spiny neurons in rat neurostriatal grafts by cortical and thalamic stimulation. J Neurophysiol 65: 477–493PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • A. Björklund
    • 1
  • K. Wictorin
    • 1
  1. 1.Department of Medical Cell Research, Section of NeurobiologyUniversity of LundLundSweden

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