Striatal Interneurons in Transgenic Nonhuman Primate Model of Huntington's Disease

Huntington's disease is an autosomal dominant neurodegenerative disorder associated with progressive motor and cognitive impairments, and the expansion of a cysteine-adenine-guanine trinucleotide (polyglutamine) repeats in exon one of the human huntingtin gene. The pathology of the disease is characterized by a profound degeneration of striatal GABAergic projection neurons with relative sparing of interneurons accompanied with astrogliosis. Here, we describe the striatal pathology in two genotypically different transgenic HD monkeys that exhibit degrees of disease progression that resembled those seen in juvenile- (rHD1) and adult-onset (rHD7) HD. The caudate nucleus and putamen underwent severe neuronal loss in both animals, while the striatal volume was reduced only in rHD1, the most severely affected monkey. The number of GABAergic (calretinin- and parvalbumin-positive) and cholinergic interneurons was also reduced in most striatal regions of these two monkeys, but to variable degrees. Overall, the density of interneurons was increased in rHD1, but not in rHD7, suggesting a relative sparing of interneurons over projection neurons in the striatum of the most affected HD monkey. The neuropil of both the caudate nucleus and putamen was invaded with reactive astrocytes in rHD1, while astrogliosis was much less severe in rHD7 and absent from control. Combined with behavioral data collected from these monkeys, our findings further demonstrate that transgenic HD monkeys share similar disease patterns with HD patients, making them a highly reliable preclinical HD animal model.