Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid

Abstract

Huntington's disease (HD) is an autosomal dominant neurological disorder characterized by progressive chorea, cognitive impairment and emotional disturbance¹. The disease usually occurs in midlife and symptoms progress inexorably to mental and physical incapacitation. It has been postulated that an excitotoxin is involved in the pathogenesis of HD^2,3. Schwarcz and colleagues have shown that quinolinic acid (QA) can produce axon-sparing lesions similar to those observed in HD^4–7. The lesions result in a depletion of neurotransmitters contained within striatal spiny neurones, for example γ-aminobutyric acid (GABA), while dopamine is unaffected. Recently, we and others have demonstrated that in HD striatum there is a paradoxical 3–5-fold increase in both somatostatin and neuropeptide Y which is attributable to selective preservation of a subclass of striatal aspiny neurones in which these peptides are co-localized^8–12. In the present study we demonstrate that lesions due to quinolinic acid closely resemble those of HD as they result in marked depletions of both GABA and substance P, with selective sparing of somatostatin/neuropeptide Y neurones. Lesions produced by kainic acid (KA), ibotenic acid (IA) and N-methyl-D-aspartate (MeAsp) were unlike those produced by QA, as they affected all cell types without sparing somatostatin/neuropeptide Y neurones. These results suggest that QA or a similar compound could be responsible for neuronal degeneration in HD.