Differential loss of striatal projection systems in Huntington’s disease: a quantitative immunohistochemical study

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Abstract

Prior studies suggest differences exist among striatal projection neuron types in their vulnerability to Huntington’s disease (HD). In the present study, we immunolabeled the fibers and terminals of the four main types of striatal projection neuron in their target areas for substance P, enkephalin, or glutamic acid decarboxylase (GAD), and used computer-assisted image analysis to quantify the abundance of immunolabeled terminals in a large sample of HD cases ranging from grade 0 to grade 4 [J. Neuropathol. Exp. Neurol. 44 (1985) 559], normalized to labeling in control human brains. Our goal was to characterize the relative rates of loss of the two striatopallidal projection systems (to the internal versus the external pallidal segments) and the two striatonigral projections systems (to pars compacta versus pars reticulata). The findings for GAD and the two neuropeptides were similar—the striatal projection to the external pallidal segment was the most vulnerable, showing substantial loss by grade 1. Loss of fibers in both subdivisions of the substantia nigra was also already great by grade 1. By contrast, the loss in the striatal projection system to the internal segment of globus pallidus proceeded more gradually. By grade 4 of HD, however, profound loss in all projection systems was apparent. These findings support the notion that the striatal neurons preferentially projecting to the internal pallidal segment are, in fact, less vulnerable in HD than are the other striatal projection neuron types.

Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive loss of movement control, often accompanied by cognitive decline and psychiatric disturbance (Roos, 1986, Martin and Gusella, 1986). Striatal projection neurons, which are GABAergic (Kita and Kitai, 1988, Reiner and Anderson, 1990), and parvalbuminergic striatal interneurons degenerate during HD (Harrington and Kowall, 1991, Ferrer et al., 1994, Vonsattel and DiFiglia, 1998), whereas cholinergic striatal interneurons, striatal interneurons co-containing somatostatin, neuropeptide Y and/or neuronal nitric oxide synthase (NOS), and medium-sized calretinergic striatal interneurons survive in HD (Ferrante et al., 1985, Ferrante et al., 1986, Ferrante et al., 1987, Albin et al., 1990a, Cicchetti and Parent, 1996, Cicchetti et al., 2000). Since projection neurons make up 95% of striatal neurons (Graybiel, 1990, Reiner and Anderson, 1990, Gerfen, 1992), their vulnerability in HD accounts for the pronounced atrophy of striatum by late HD.

While many striatal projection neurons collateralize to more than one target, anterograde labeling studies of single striatal axons and retrograde labeling studies from striatal target areas show that striatal projection neurons can be subdivided into four major populations based on their primary projection target: (1) those projecting only or mainly to the external segment of globus pallidus (GPe), which are typically rich in enkephalin (ENK) and poor in or devoid of substance P (SP), and located in the striatal matrix compartment; (2) those projecting mainly to the internal segment of globus pallidus (GPi), which are rich in SP but poor in ENK, and located in the striatal matrix compartment; (3) those projecting mainly to the substantia nigra pars reticulata (SNr), which are also rich in SP and typically poor in ENK, and located in the striatal matrix compartment; and (4) those projecting to the substantia nigra pars compacta (SNc), which also are rich in SP and typically poor in ENK, and largely localized to the striatal patch compartment (Feger and Crossman, 1984, Loopuijt and van der Kooy, 1985, Beckstead and Cruz, 1986, Parent et al., 1989, Graybiel, 1990, Kawaguchi et al., 1990, Reiner and Anderson, 1990, Selemon and Goldman-Rakic, 1990, Parent et al., 1995, Reiner et al., 1999, Wu et al., 2000). The perikarya of striato-GPe neurons and their terminals in GPe are also enriched in D2 dopamine and A2a adenosine receptors (Schiffmann et al., 1991, Fink et al., 1992, Le Moine and Bloch, 1995). In turn, the perikarya of striato-GPi neurons and their terminals in GPi are enriched in D1 dopamine receptors, as are the perikarya of striatonigral neurons and their terminals in substantia nigra (Schiffmann et al., 1991, Fink et al., 1992, Le Moine and Bloch, 1995). All striatal projection neuron perikarya and terminals also possess cannabinoid receptors (Herkenham et al., 1991, Mailleux and Vanderhaeghen, 1992, Glass et al., 1997).

Localization of the above projection neuron type-selective markers has been used to determine if the different populations of striatal projection neurons differ from one another in their vulnerability in HD. Our own previous immunohistochemical studies of terminals in striatal target areas have indicated that ENK+ terminals in GPe and SP+ terminals in the substantia nigra appear to be lost more rapidly during HD progression than are SP+ terminals in GPi (Reiner et al., 1988, Albin et al., 1990a, Albin et al., 1990b, Albin et al., 1992). The preferential sparing of striatal input to GPi has been supported by neuropeptide immunolabeling (Sapp et al., 1995), and by ligand binding for D1 and D2 dopamine (Glass et al., 2000), cannabinoid (Richfield and Herkenham, 1994, Glass et al., 2000), and A2a adenosine receptors (Glass et al., 2000). The various findings on loss of striatal terminal markers have been interpreted to indicate that striato-GPi neurons are more resistant in HD than are striato-GPe or striatonigral neurons (Reiner et al., 1988, Sapp et al., 1995). Direct support for this premise at the perikaryal level has come from in situ hybridization histochemistry of SP and ENK mRNA in HD striatum (Albin et al., 1991, Richfield et al., 1995a, Richfield et al., 1995b), and from binding of D1 and D2 dopamine (Glass et al., 2000) and A2a adenosine receptors (Glass et al., 2000) in HD striatum.

Other studies, however, have reported no difference in the relative loss of immunoreactivity for SP and ENK in striatal terminals in GPe and GPi, as detected by immunohistochemistry (Marshall et al., 1983, Zech and Bogerts, 1985, Ferrante et al., 1990) or radioimmunoassay (Storey and Beal, 1993), while yet others have reported a more marked loss of SP than ENK (Grafe et al., 1985, Emson et al., 1980). Biochemical studies of GABA and its synthesizing enzyme, glutamic acid decarboxylase (GAD), have also been used to characterize projection neuron loss in HD (Spokes, 1980, Spokes et al., 1979, Reynolds and Pearson, 1990, Storey and Beal, 1993). While some of these studies have reported lesser vulnerability of the striato-GPi projections than striato-GPe and striatonigral, others have reported results conflicting with these.

In the present study, we immunolabeled fibers and terminals of the different striatal projection systems for their neuropeptide content (SP or ENK), as well as for GAD, in a number of cases at each of the neuropathological grades of HD (Vonsattel et al., 1985) and in control cases. By quantifying residual fiber abundance, using computer-assisted image analysis as in similar prior studies of HD and animal models of HD (Figueredo-Cardenas et al., 1994; Sapp et al., 1995, Meade et al., 2000), we sought to provide further insight into the occurrence and pace of differential projection system loss in HD. While preferential survival of the striato-GPi projection was a focus of this study, possible differences among the striato-GPe, the striato-SNc and striato-SNr projections, which are as yet unresolved (Reiner et al., 1988, Albin et al., 1990a, Albin et al., 1990b, Albin et al., 1992, Hedreen and Folstein, 1995), were also of interest. We found that the striato-GPi projection is far less vulnerable than the striato-GPe, striato-SNr and striato-SNc projections, with no major differences evident among the latter three.

Section snippets

Subjects and tissues

Coronal tissue blocks or slide-mounted sections containing globus pallidus (GP) or substantia nigra (SN) were obtained for 36 HD cases (male = 15, female = 21) that were verified by pathology, symptoms and family history, with ages ranging from 11 to 87 years (mean age = 50.7 ± 3.2) (Table 1). Fourteen of these were obtained from the University of Michigan Medical Center (Ann Arbor, MI), eight were from the National Neurological Resource Bank (NNRB, Los Angeles, CA), six were from the Brain

Control cases

The neurologically normal control specimens had dense plexuses of SP+ fibers in GPi, but only a few SP+ fibers in GPe (Fig. 5). Conversely, ENK+ fibers were abundant in GPe but sparse in GPi (Fig. 5). At high magnification (Fig. 6), the SP+ and ENK+ fiber plexuses in globus pallidus had the ‘woolly fiber’ pattern characteristic of striatopallidal terminals (Haber and Elde, 1981, Haber and Elde, 1982, Haber and Nauta, 1983, Reiner et al., 1999). The GPi and GPe in neurologically normal control

Discussion

The present findings expand on previous reports that striato-GPe and striato-SN projections are more severely affected than striato-GPi in early and middle grades of HD (Reiner et al., 1988, Albin et al., 1989, Albin et al., 1990a, Albin et al., 1990b, Albin et al., 1991, Richfield et al., 1995a, Richfield et al., 1995b, Sapp et al., 1995, Augood et al., 1996). Since each striatal projection target receives its major input from a distinct set of striatal projection neurons (Feger and Crossman,

Acknowledgements

We thank Debbie Romeo and Ellen Karle for their excellent technical assistance. We are also grateful to Drs. Marian DiFiglia and Eric Richfield for providing us with tissues from the Massachusetts General Hospital and the University of Rochester, respectively. This research was supported by NS01300, NS38166, and a VA Merit Review Grant (RLA), NS19613 (ABY and JBP), the Hereditary Disease Foundation (KDA, AR), The Neuroscience Center of Excellence of the University of Tennessee (KDA), a Cure HD

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