Synaptic Abnormalities Associated with Huntington’s Disease

  • Austen J. Milnerwood
  • Lynn A. Raymond

1. Summary

In the little over a decade since the causal mutation in Huntington’s disease (HD) was first identified, over a dozen genetic mouse models, as well as a variety of cell and invertebrate models, of HD have been produced. These models are continually enhancing our understanding of the varied roles of normal and mutated huntingtin proteins. This ubiquitously expressed and multi-functional protein has been found to be involved in a growing number of protein-protein interactions that, when dysfunctional, can have dire consequences for neuronal function and survival. The clinical features of HD have been regarded traditionally as resulting from neurodegeneration. Recent advances suggest that synaptic dysfunction may be the first detectable effect of the HD mutation and correlate with early clinical signs and symptoms of the disease. Moreover, mechanisms underlying synaptic dysfunction may also contribute to selective neuronal vulnerability in HD. Further investigation in this area will likely lead to novel therapies to treat symptoms, as well as to potentially delay onset and slow progression, of this devastating disorder.


NMDAR Function Selective Neuronal Vulnerability Striatal MSNs 
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8. References

  1. 1.
    Huntington’s Disease Collaborative Research Group. (1993) Cell 72, 971–983.CrossRefGoogle Scholar
  2. 2.
    Vonsattel, J.P., Myers, R.H., Stevens, T.J., Ferrante, R.J., Bird, E.D., and Richardson, E.P., Jr. (1985) J Neuropathol Exp Neurol 44, 559–577.PubMedGoogle Scholar
  3. 3.
    Levine, M.S., Cepeda, C., Hickey, M.A., Fleming, S.M., and Chesselet, M.F. (2004) Trends Neurosci 27, 691–697.PubMedCrossRefGoogle Scholar
  4. 4.
    DiFiglia, M., Sapp, E., Chase, K., Schwarz, C., Meloni, A., Young, C., Martin, E., Vonsattel, J.P., Carraway, R., Reeves, S.A., et al. (1995) Neuron 14, 1075–1081.PubMedCrossRefGoogle Scholar
  5. 5.
    Aronin, N., Chase, K., Young, C., Sapp, E., Schwarz, C., Matta, N., Kornreich, R., Landwehrmeyer, B., Bird, E., Beal, M.F., et al. (1995) Neuron 15, 1193–1201.PubMedCrossRefGoogle Scholar
  6. 6.
    Landwehrmeyer, G.B., McNeil, S.M., Dure, L.S.T., Ge, P., Aizawa, H., Huang, Q., Ambrose, C.M., Duyao, M.P., Bird, E.D., Bonilla, E., de Young, M., Avila-Gonzales, A.J., Wexler, N.S., DiFiglia, M., Gusella, J.F., MacDonald, M.E., Penney, J.B., Young, A.B., and Vonsattel, J.-P. (1995) Ann Neurol 37, 218–230.PubMedCrossRefGoogle Scholar
  7. 7.
    Reiner, A., Dragatsis, I., Zeitlin, S., and Goldowitz, D. (2003) Mol Neurobiol 28, 259–276.PubMedCrossRefGoogle Scholar
  8. 8.
    Li, H., Li, S.H., Yu, Z.X., Shelbourne, P., and Li, X.J. (2001) J Neurosci 21, 8473–8481.PubMedGoogle Scholar
  9. 9.
    Gunawardena, S., Her, L.S., Brusch, R.G., Laymon, R.A., Niesman, I.R., Gordesky-Gold, B., Sintasath, L., Bonini, N.M., and Goldstein, L.S. (2003) Neuron 40, 25–40.PubMedCrossRefGoogle Scholar
  10. 10.
    Szebenyi, G., Morfini, G.A., Babcock, A., Gould, M., Selkoe, K., Stenoien, D.L., Young, M., Faber, P.W., MacDonald, M.E., McPhaul, M.J., and Brady, S.T. (2003) Neuron 40, 41–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Trushina, E. et al. (2004) Mol Cell Biol 24, 8195–8209.PubMedCrossRefGoogle Scholar
  12. 12.
    Li, X.J., Li, S.H., Sharp, A.H., Nucifora, F.C., Jr., Schilling, G., Lanahan, A., Worley, P., Snyder, S.H., and Ross, C.A. (1995) Nature 378, 398–402.PubMedCrossRefGoogle Scholar
  13. 13.
    Martin, E.J., Kim, M., Velier, J., Sapp, E., Lee, H.S., Laforet, G., Won, L., Chase, K., Bhide, P.G., Heller, A., Aronin, N., and Difiglia, M. (1999) J Comp Neurol 403, 421–430.PubMedCrossRefGoogle Scholar
  14. 14.
    Engelender, S., Sharp, A.H., Colomer, V., Tokito, M.K., Lanahan, A., Worley, P., Holzbaur, E.L., and Ross, C.A. (1997) Hum Mol Genet 6, 2205–2212.PubMedCrossRefGoogle Scholar
  15. 15.
    Gauthier, L.R., Charrin, B.C., Borrell-Pages, M., Dompierre, J.P., Rangone, H., Cordelieres, F.P., De Mey, J., MacDonald, M.E., Lessmann, V., Humbert, S., and Saudou, F. (2004) Cell 118, 127–138.PubMedCrossRefGoogle Scholar
  16. 16.
    Li, H., Wyman, T., Yu, Z.X., Li, S.H., and Li, X.J. (2003) Hum Mol Genet 12, 2021–2030.PubMedCrossRefGoogle Scholar
  17. 17.
    Usdin, M.T., Shelbourne, P.F., Myers, R.M., and Madison, D.V. (1999) Hum Mol Genet 8, 839–846.PubMedCrossRefGoogle Scholar
  18. 18.
    Cepeda, C., Hurst, R.S., Calvert, C.R., Hernandez-Echeagaray, E., Nguyen, O.K., Jocoy, E., Christian, L.J., Ariano, M.A., and Levine, M.S. (2003) J Neurosci 23, 961–969.PubMedGoogle Scholar
  19. 19.
    Sudhof, T.C. (2004) Annu Rev Neurosci 27, 509–547.PubMedCrossRefGoogle Scholar
  20. 20.
    Liévens, J.C., Woodman, B., Mahal, A., and Bates, G.P. (2002) Mol Cell Neurosci 20, 638–648.PubMedCrossRefGoogle Scholar
  21. 21.
    Bibb, J.A., Yan, Z., Svenningsson, P., Snyder, G.L., Pieribone, V.A., Horiuchi, A., Nairn, A.C., Messer, A., and Greengard, P. (2000) Proc Natl Acad Sci U S A 97, 6809–6814.PubMedCrossRefGoogle Scholar
  22. 22.
    Smith, R., Petersen, A., Bates, G.P., Brundin, P., and Li, J.Y. (2005) Neurobiol Dis 20, 673–684.PubMedCrossRefGoogle Scholar
  23. 23.
    Morton, A.J., and Edwardson, J.M. (2001) J Neurochem 76, 166–172.PubMedCrossRefGoogle Scholar
  24. 24.
    DiProspero, N.A., Chen, E.Y., Charles, V., Plomann, M., Kordower, J.H., and Tagle, D.A. (2004) J Neurocytol 33, 517–533.PubMedCrossRefGoogle Scholar
  25. 25.
    Edwardson, J.M., Wang, C.T., Gong, B., Wyttenbach, A., Bai, J., Jackson, M.B., Chapman, E.R., and Morton, A.J. (2003) J Biol Chem 278, 30849–30853.PubMedCrossRefGoogle Scholar
  26. 26.
    Freeman, W., and Morton, A.J. (2004) Brain Res Bull 63, 45–55.PubMedCrossRefGoogle Scholar
  27. 27.
    Lione, L.A., Carter, R.J., Hunt, M.J., Bates, G.P., Morton, A.J., and Dunnett, S.B. (1999) J Neurosci 19, 10428–10437.PubMedGoogle Scholar
  28. 28.
    Reim, K., Mansour, M., Varoqueaux, F., McMahon, H.T., Sudhof, T.C., Brose, N., and Rosenmund, C. (2001) Cell 104, 71–81.PubMedCrossRefGoogle Scholar
  29. 29.
    Takahashi, S., Ujihara, H., Huang, G.Z., Yagyu, K.I., Sanbo, M., Kaba, H., and Yagi, T. (1999) Eur J Neurosci 11, 2359–2366.PubMedCrossRefGoogle Scholar
  30. 30.
    Murphy, K.P.S.J., Carter, R.J., Lione, L.A., Mangiarini, L., Mahal, A., Bates, G.P., Dunnett, S.B., and Morton, A.J. (2000) J Neurosci 20, 5115–5123.PubMedGoogle Scholar
  31. 31.
    Glynn, D., Bortnick, R.A., and Morton, A.J. (2003) Hum Mol Genet 12, 2431–2448.PubMedCrossRefGoogle Scholar
  32. 32.
    Miller, L.C., Swayne, L.A., Chen, L., Feng, Z.P., Wacker, J.L., Muchowski, P.J., Zamponi, G.W., and Braun, J.E. (2003) J Biol Chem 278, 53072–53081.PubMedCrossRefGoogle Scholar
  33. 33.
    Wanker, E.E., Rovira, C., Scherzinger, E., Hasenbank, R., Walter, S., Tait, D., Colicelli, J., and Lehrach, H. (1997) Hum Mol Genet 6, 487–495.PubMedCrossRefGoogle Scholar
  34. 34.
    Kalchman, M.A., Koide, H.B., McCutcheon, K., Graham, R.K., Nichol, K., Nishiyama, K., Kazemi-Esfarjani, P., Lynn, F.C., Wellington, C., Metzler, M., Goldberg, Y.P., Kanazawa, I., Gietz, R.D., and Hayden, M.R. (1997) Nat Genet 16, 44–53.PubMedCrossRefGoogle Scholar
  35. 35.
    Metzler, M., Legendre-Guillemin, V., Gan, L., Chopra, V., Kwok, A., McPherson, P.S., and Hayden, M.R. (2001) J Biol Chem 276, 39271–39276.PubMedCrossRefGoogle Scholar
  36. 36.
    Modregger, J., DiProspero, N.A., Charles, V., Tagle, D.A., and Plomann, M. (2002) Hum Mol Genet 11, 2547–2558.PubMedCrossRefGoogle Scholar
  37. 37.
    Arzberger, T., Krampfl, K., Leimgruber, S., and Weindl, A. (1997) J Neuropathol Exp Neurol 56, 440–454.PubMedGoogle Scholar
  38. 38.
    Behrens, P.F., Franz, P., Woodman, B., Lindenberg, K.S., and Landwehrmeyer, G.B. (2002) Brain 125, 1908–1922.PubMedCrossRefGoogle Scholar
  39. 39.
    Nicniocaill, B., Haraldsson, B., Hansson, O., O’Connor, W.T., and Brundin, P. (2001) Eur J Neurosci 13, 206–210.PubMedCrossRefGoogle Scholar
  40. 40.
    Li, L., Murphy, T.H., Hayden, M.R., and Raymond, L.A. (2004) J Neurophysiol 92, 2738–2746.PubMedCrossRefGoogle Scholar
  41. 41.
    Morton, A.J., Hunt, M.J., Hodges, A.K., Lewis, P.D., Redfern, A.J., Dunnett, S.B., and Jones, L. (2005) Eur J Neurosci 21, 855–870.PubMedCrossRefGoogle Scholar
  42. 42.
    Ferrante, R.J., Kowall, N.W., and Richardson, E.P., Jr. (1991) J Neurosci 11, 3877–3887.PubMedGoogle Scholar
  43. 43.
    Cepeda, C., Ariano, M.A., Calvert, C.R., Flores-Hernandez, J., Chandler, S.H., Leavitt, B.R., Hayden, M.R., and Levine, M.S. (2001) J Neurosci Res 66, 525–539.PubMedCrossRefGoogle Scholar
  44. 44.
    Cepeda, C., Starling, A.J., Wu, N., Nguyen, O.K., Uzgil, B., Soda, T., Andre, V.M., Ariano, M.A., and Levine, M.S. (2004) J Neurosci Res 78, 855–867.PubMedCrossRefGoogle Scholar
  45. 45.
    Klapstein, G.J., Fisher, R.S., Zanjani, H., Cepeda, C., Jokel, E.S., Chesselet, M.F., and Levine, M.S. (2001) J Neurophysiol 86, 2667–2677.PubMedGoogle Scholar
  46. 46.
    Levine, M.S., Klapstein, G.J., Koppel, A., Gruen, E., Cepeda, C., Vargas, M.E., Jokel, E.S., Carpenter, E.M., Zanjani, H., Hurst, R.S., Efstratiadis, A., Zeitlin, S., and Chesselet, M.F. (1999) J Neurosci Res 58, 515–532.PubMedCrossRefGoogle Scholar
  47. 47.
    Ariano, M.A., Cepeda, C., Calvert, C.R., Flores-Hernandez, J., Hernandez-Echeagaray, E., Klapstein, G.J., Chandler, S.H., Aronin, N., DiFiglia, M., and Levine, M.S. (2005) J Neurophysiol 93, 2565–2574.PubMedCrossRefGoogle Scholar
  48. 48.
    Yohrling IV, G.J., and Cha, J.H. (2002) in Huntington’s Disease (Bates, G.P., Harper, P.S., and Jones, L., eds), Third Ed., pp. 276–308, Oxford University Press, Oxford.Google Scholar
  49. 49.
    Jarabek, B.R., Yasuda, R.P., and Wolfe, B.B. (2004) Brain 127, 505–516.PubMedCrossRefGoogle Scholar
  50. 50.
    Hansson, O., Guatteo, E., Mercuri, N.B., Bernardi, G., Li, X.J., Castilho, R.F., and Brundin, P. (2001) Eur J Neurosci 14, 1492–1504.PubMedCrossRefGoogle Scholar
  51. 51.
    Petersén, Å., Chase, K., Puschban, Z., DiFiglia, M., Brundin, P., and Aronin, N. (2002) Exp Neurol 175, 297–300.PubMedCrossRefGoogle Scholar
  52. 52.
    Zeron, M.M., Hansson, O., Chen, N., Wellington, C.L., Leavitt, B.R., Brundin, P., Hayden, M.R., and Raymond, L.A. (2002) Neuron 33, 849–860.PubMedCrossRefGoogle Scholar
  53. 53.
    Bezprozvanny, I., and Hayden, M.R. (2004) Biochem Biophys Res Commun 322, 1310–1317.PubMedCrossRefGoogle Scholar
  54. 54.
    Anborgh, P.H., Godin, C., Pampillo, M., Dhami, G.K., Dale, L.B., Cregan, S.P., Truant, R., and Ferguson, S.S. (2005) J Biol Chem 280, 34840 34848.PubMedCrossRefGoogle Scholar
  55. 55.
    Kuppenbender, K.D., Standaert, D.G., Feuerstein, T.J., Penney, J.B., Jr., Young, A.B., and Landwehrmeyer, G.B. (2000) J Comp Neurol 419, 407–421.PubMedCrossRefGoogle Scholar
  56. 56.
    Chen, N., Luo, T., Wellington, C., Metzler, M., McCutcheon, K., Hayden, M.R., and Raymond, L.A. (1999) J Neurochem 72, 1890–1898.PubMedCrossRefGoogle Scholar
  57. 57.
    Laforet, G.A., Sapp, E., Chase, K., McIntyre, C., Boyce, F.M., Campbell, M., Cadigan, B.A., Warzecki, L., Tagle, D.A., Reddy, P.H., Cepeda, C., Calvert, C.R., Jokel, E.S., Klapstein, G.J., Ariano, M.A., Levine, M.S., DiFiglia, M., and Aronin, N. (2001) J Neurosci 21, 9112–9123.PubMedGoogle Scholar
  58. 58.
    Zeron, M.M., Fernandes, H.B., Krebs, C., Shehadeh, J., Wellington, C.L., Leavitt, B.R., Baimbridge, K.G., Hayden, M.R., and Raymond, L.A. (2004) Mol Cell Neurosci 25, 469–479.PubMedCrossRefGoogle Scholar
  59. 59.
    Shehadeh, J., Fernandes, H.B., Zeron Mullins, M.M., Graham, R.K., Leavitt, B.R., Hayden, M.R., and Raymond, L.A. (2006) Neurobiol Dis 21, 392–403.PubMedCrossRefGoogle Scholar
  60. 60.
    Luthi-Carter, R., Apostol, B.L., Dunah, A.W., DeJohn, M.M., Farrell, L.A., Bates, G.P., Young, A.B., Standaert, D.G., Thompson, L.M., and Cha, J.H. (2003) Neurobiol Dis 14, 624–636.PubMedCrossRefGoogle Scholar
  61. 61.
    Li, L., Fan, M., Icton, C.D., Chen, N., Leavitt, B.R., Hayden, M.R., Murphy, T.H., and Raymond, L.A. (2003) Neurobiol Aging 24, 1113–1121.PubMedCrossRefGoogle Scholar
  62. 62.
    Prybylowski, K., and Wenthold, R.J. (2004) J Biol Chem 279, 9673–9676.PubMedCrossRefGoogle Scholar
  63. 63.
    Migaud, M., Charlesworth, P., Dempster, M., Webster, L.C., Watabe, A.M., Makhinson, M., He, Y., Ramsay, M.F., Morris, R.G., Morrison, J.H., O’Dell, T.J., and Grant, S.G. (1998) Nature 396, 433–439.PubMedCrossRefGoogle Scholar
  64. 64.
    Ehrlich, I., and Malinow, R. (2004) J Neurosci 24, 916–927.PubMedCrossRefGoogle Scholar
  65. 65.
    Sattler, R., Xiong, Z., Lu, W.Y., Hafner, M., MacDonald, J.F., and Tymianski, M. (1999) Science 284, 1845–1848.PubMedCrossRefGoogle Scholar
  66. 66.
    Sun, Y., Savanenin, A., Reddy, P.H., and Liu, Y.F. (2001) J Biol Chem 276, 24713–24718.PubMedCrossRefGoogle Scholar
  67. 67.
    Song, C., Zhang, Y., Parsons, C.G., and Liu, Y.F. (2003) J Biol Chem 278, 33364–33369.PubMedCrossRefGoogle Scholar
  68. 68.
    Huang, K., and El-Husseini, A. (2005) Curr Opin Neurobiol 15, 527–535.PubMedCrossRefGoogle Scholar
  69. 69.
    Hardingham, G.E., and Bading, H. (2002) Biochim Biophys Acta 1600, 148–153.PubMedGoogle Scholar
  70. 70.
    Ariano, M.A., Wagle, N., and Grissell, A.E. (2005) J Neurosci Res 80, 634–645.PubMedCrossRefGoogle Scholar
  71. 71.
    Kim, M., Velier, J., Chase, K., Laforet, G., Kalchman, M.A., Hayden, M.R., Won, L., Heller, A., Aronin, N., and Difiglia, M. (1999) Neuroscience 89, 1159–1167.PubMedCrossRefGoogle Scholar
  72. 72.
    Greengard, P. (2001) Science 294, 1024–1030.PubMedCrossRefGoogle Scholar
  73. 73.
    Crossman, A.R. (2000) J Anat 196, 519–525.PubMedCrossRefGoogle Scholar
  74. 74.
    Gutekunst, C., Norflus, F., and Hersch, S.M. (2002) in Huntington’s Disease (Bates, G.P., Harper, P.S., and Jones, L., eds), Third Ed., pp. 251–275, Oxford University Press, Oxford.Google Scholar
  75. 75.
    Piccini, P. (2004) Curr Opin Neurol 17, 459–466.PubMedCrossRefGoogle Scholar
  76. 76.
    Ariano, M.A., Aronin, N., Difiglia, M., Tagle, D.A., Sibley, D.R., Leavitt, B.R., Hayden, M.R., and Levine, M.S. (2002) J Neurosci Res 68, 716–729.PubMedCrossRefGoogle Scholar
  77. 77.
    Zucker, B., Luthi-Carter, R., Kama, J.A., Dunah, A.W., Stern, E.A., Fox, J.H., Standaert, D.G., Young, A.B., and Augood, S.J. (2005) Hum Mol Genet 14, 179–189.PubMedCrossRefGoogle Scholar
  78. 78.
    Kennedy, L., Shelbourne, P.F., and Dewar, D. (2005) Brain Res 1039, 14–21.PubMedCrossRefGoogle Scholar
  79. 79.
    Naver, B., Stub, C., Møller, M., Fenger, K., Hansen, A.K., Hasholt, L., and Sørensen, S.A. (2003) Neuroscience 122, 1049–1057.PubMedCrossRefGoogle Scholar
  80. 80.
    Tepper, J.M., and Bolam, J.P. (2004) Curr Opin Neurobiol 14, 685–692.PubMedCrossRefGoogle Scholar
  81. 81.
    Kittler, J.T., Thomas, P., Tretter, V., Bogdanov, Y.D., Haucke, V., Smart, T.G., and Moss, S.J. (2004) Proc Natl Acad Sci U S A 101, 12736–12741.PubMedCrossRefGoogle Scholar
  82. 82.
    Milner, B., Squire, L.R., and Kandel, E.R. (1998) Neuron 20, 445–468.PubMedCrossRefGoogle Scholar
  83. 83.
    Morris, R. G.M., Moser, E.I., Riedel, G., Martin, S.J., Sandin, J., Day, M., and O’Carroll, C. (2003) Philos Trans R Soc Lond B Biol Sci 358, 773–786.PubMedCrossRefGoogle Scholar
  84. 84.
    Hodgson, J.G., Agopyan, N., Gutekunst, C.A., Leavitt, B.R., LePiane, F., Singaraja, R., Smith, D.J., Bissada, N., McCutcheon, K., Nasir, J., Jamot, L., Li, X.J., Stevens, M.E., Rosemond, E., Roder, J.C., Phillips, A.G., Rubin, E.M., Hersch, S.M., and Hayden, M.R. (1999) Neuron 23, 181–192.PubMedCrossRefGoogle Scholar
  85. 85.
    Cybulska-Klosowicz, A., Mazarakis, N.K., Van Dellen, A., Blakemore, C., Hannan, A.J., and Kossut, M. (2004) Neurobiol Dis 17, 427–434.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Austen J. Milnerwood
    • 1
  • Lynn A. Raymond
    • 1
  1. 1.Department of Psychiatry and Brain Research CentreUniversity of British ColumbiaVancouverCanada

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