Abnormalities of Striatal Projection Neurons andN-Methyl-D-Aspartate Receptors in Presymptomatic Huntington's Disease

Abstract

HUNTINGTON'S disease is an autosomal dominant disease characterized by slowly progressive personality changes, dementia, and movement disorders.^{1 , 2} The average age at onset is 30 to 40 years, and the disease lasts for an average of 15 to 20 years. Analysis with restriction-fragmentlength polymorphisms (RFLPs) has localized the Huntington's disease gene close to the telomere of the short arm of chromosome 4.^{1 2 3} Prominent striatal atrophy with loss of striatal neurons and relative sparing of fibers of passage and afferent axons is the pathological hallmark of Huntington's disease.⁴ Recent studies have demonstrated a distinct pattern of vulnerability of striatal neurons in Huntington's disease. Striatal cholinergic interneurons (neurons whose axons terminate entirely within the striatum) and striatal interneurons containing somatostatin or neuropeptide Y ( Fig. 1 ) are largely spared in Huntington's disease.^{5 6 7 8} Projection neurons, whose axons terminate in regions outside the striatum ( Fig. 1 ), predominate in the striatum,⁹ and subpopulations of striatal projection neurons are preferentially affected during the course of the disease.^{10 11 12} These subpopulations are defined on the basis of their target region and the neuropeptides they contain ( Fig. 1 ). In Huntington's disease, there is early loss of enkephalinergic neurons projecting to the external globus pallidus and neurons containing substance P projecting to the substantia nigra pars reticulata. Neurons containing substance P that project to the internal globus pallidus or the substantia nigra pars compacta are lost late in the disease. This sequence of degeneration of the striatal projection neurons correlates with the evolution of some of the motor and oculomotor abnormalities characteristic of Huntington's disease.^{10 , 12 , 13}