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

Abstract

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.

Figure 1

(A,B) Stereological counts of Nissl-stained neurons of the head and body of the caudate nucleus and in the pre- and post-commissural putamen in the two HD monkeys (rHD1, rHD7) and the control monkey (rWT1). (C,D) Volume calculations of the caudate nucleus and putamen from the Nissl-stained slices in the same animals. The CE for the volume calculations was at or below 0.02 for all measurement above.

Figure 2

(A–F) Estimated total number of CR+ cells (A,B), PV+ cells (C,D) and ChAT+ cells (E,F) in the caudate nucleus and putamen of the two HD monkeys (rHD1, rHD7) and the control animal (rWT1). The CE was at or below 0.08 for all measurements shown above.

Figure 3

(A–F) Estimated density of CR+ cells (A,B), PV+ cells (C,D), and ChAT+ cells (E,F) in the caudate nucleus and putamen of the two HD monkeys (rHD1, rHD7) and the control animal (rWT1).

Figure 4

(A–C) Light microscope images depicting the differences in density of CR+ cells in the caudate head between the two transgenic HD (rHD1, rHD7) and WT (rWT1) monkeys. The scale bar in A represents 5 μm. (D–L) Light microscope images depicting examples of striatal CR+, PV+, and ChAT+ neurons in each monkey. The scale bar in J represents 10 μm.

Figure 5

(A–H) Light micrographs showing astrocytic GFAP labeling in the caudate nucleus (CD; A–D) and putamen (PU; E–H) of the two transgenic HD monkeys (rHD1, rHD7) and the control animal (rWT1). Note the large density of labeled astrocytes in the CD and PU of the most severely affected HD monkey (rHD1-A,E) compared with the least affected HD monkey (rHD7; B,C; F–G) and the control (D,H). In the CD of rHD7, GFAP-immunostained elements were confined to the membrane of blood vessels (B), with very rare instances of labeled neuropil astrocytes (C), while in the PU, a modest number of immunoreactive astrocytes could be seen, predominantly in the ventral tier of the structure (G). Scale bar in A: 30 um in A and E; 20 um in (B–D and F–H).