DIRECT AND INDIRECT EXCITOTOXIC MODELS OF HUNTINGTONS-DISEASE - A REVIEW

Although the genetic mutation responsible for Huntington's disease (HD ) has been characterized, the mechanism by which it results in neurona l death remains unknown. Animal models that imitate the clinical and n europathological features of HD are useful for investigating potential pathophysiological mechanisms and therapeutic strategies. Although th e disease process eventually extends to extrastriatal cerebral structu res (globus pallidus, cerebral cortex, thalamus), many lines of eviden ce suggest that HD primarily affects the Golgi Type II neurons of the striatum. The affected extrastriatal areas are connected to the striat um, and their involvement is secondary to the primary striatal abnorma lities. Selective damage to the striatum is therefore the key to creat ion of animal models of PID. Direct and in direct excitotoxic striatal lesions can be produced in rats and nonhuman primates. Direct lesions can be obtained via a unilateral injection into the striatum of an ex citotoxin chosen based on its selective toxic effects on the targeted neuronal population. The neuropathologic lesions induced in rats by ex citotoxins such as ibotenic acid or quinolinic acid are fairly similar to those seen in HD, although the motor disorders do not include dyst onia or chorea. In baboons, the same type of lesion produces comparabl e neuropathologic features, and when a dopamine receptor agonist is th en given, a dyskinetic syndrome similar to that seen in HD develops, w ith hyperkinesia, chorea, dystonia, posture disorders, and head and or ofacial dyskinesia. Indirect excitotoxic lesions of the striatum can b e produced by administration of a mitochondrial toxin. Systemic admini stration of the irreversible succinate dehydrogenase inhibitor 3-nitro propionic acid (3-NP) selectively induces bilateral lesions of the str iatum. Chronic 3-NP administration to nonhuman primates is associated with spontaneous movement disorders, including dystonia and chorea, an d with frontal cognitive disorders due to alterations in the frontostr iatal pathway secondary to lesions of the caudate nucleus demonstrable by magnetic resonance imaging. Thus, this model replicates the cardin al manifestations of HD, namely spontaneous movement disorders, gradua l degenerescence of striatal neurones, and frontal cognitive disorders .