Excitotoxicity in Huntington’s Disease

  • M. Flint Beal


There is a large body of evidence implicating excitotoxicity in Huntington’s Disease (HD) pathogenesis. The concept that excitotoxicity might playa role was developed after the observation that kainic acid induced striatal lesions which mimic many of the neuropathologic features of HD. We and others subsequently showed that quinolinic acid lesions, which spare NADPH-diaphorase neurons, produced an improved excitotoxic model. There however is no evidence for an increase in excitatory amino acids in HD brain tissue. Subsequent studies by ourselves and others demonstrated that mitochondrial toxins could produce striatal lesions, which are mediated by excitotoxicity. A defect in energy metabolism sensitizes cells to excitatory amino acids. We found that 3-nitropropionic acid lesions produce a model of HD in both rodents and primates, which mimics not only the neuropathologic features but also the motor and cognitive deficits, which occur in HD. The development of transgenic mouse models has furthered the evidence that excitotoxicity plays a role in HD pathogenesis. Although mice with short fragments of huntingtin show resistance to excitotoxic lesions, transgenic mice with full-length huntingtin show increased sensitivity to quinolinic acid lesions. Cultured medium spiny neurons expressing full-length huntingtin with 72 repeats, also demonstrate enhanced excitotoxicity, which is abolished by NR28 subunits specific antagonists such as, ifenprodil. There is, therefore, substantial evidence that excitotoxicity plays a critical role in HD pathogenesis.


Huntington’s disease excitotoxicity free radicals nitric oxide animal models 


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Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • M. Flint Beal
    • 1
  1. 1.Department of Neurology and NeuroscienceWeill Medical College of Cornell University, New York Presbyterian HospitalNew YorkUSA

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