Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington's disease using high resolution image analysis

Sapp, Ellen; Ge, Pei; Aizawa, Hitoshi; Bird, E. D.; Penney, John B.; Young, Anne B.; Vonsattel, Jean‐Paul; DiFiglia, Marian

doi:10.1016/0306-4522(94)00427-7

Cited by 147 publications

(107 citation statements)

References 19 publications

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“…A selective reduction in the expression of enkephalin but not substance P was observed in HD mice. Preferential loss of enkephalin in the striatal tissue of HD patients has been reported previously (48,49).…”

Section: Discussionmentioning

confidence: 82%

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Bibb

Yan

Svenningsson

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

263

212

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In Huntington's disease (HD), mutation of huntingtin causes selective neurodegeneration of dopaminoceptive striatal medium spiny neurons. Transgenic HD model mice that express a portion of the diseasecausing form of human huntingtin develop a behavioral phenotype that suggests dysfunction of dopaminergic neurotransmission. Here we show that presymtomatic mice have severe deficiencies in dopamine signaling in the striatum. These include selective reductions in total levels of dopamine-and cAMP-regulated phosphoprotein, Mr 32 kDA (DARPP-32) and other dopamine-regulated phosphoprotein markers of medium spiny neurons. HD mice also show defects in dopamine-regulated ion channels and in the D1 dopamine͞DARPP-32 signaling cascade. These presymptomatic defects may contribute to HD pathology. H untington's disease (HD) is an inherited neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive disturbances. The motor disturbance begins subtly, as minor adventitious movements, and gradually progresses until the entire body is consumed in flagrant chorea and uncontrolled writhing, leading to death 10-20 years after onset (1). HD pathology is characterized by specific neurodegeneration of the caudate nucleus and putamen (2, 3). Genetic analysis has established a causative link between HD and abnormal expansion of a polyglutamine repeat in the protein huntingtin (4). The transgenic mouse line R6͞2 (HD mice) is a well-characterized animal model of HD in which a fragment of a disease-causing variant of human huntingtin is ectopically expressed. These mice exhibit HD-like behavioral changes beginning after 8 weeks of life, progressively deteriorate over the succeeding 10 weeks, and die prematurely (5, 6). Although the HD mice are essentially asymptomatic until week 8, behavioral deficits are preceded by the appearance of intranuclear inclusion bodies in the central nervous system (7,8). These inclusions are similar to those detected in HD and other diseases associated with polyglutamine expansions (7-9).Both normal and mutant huntingtin are expressed throughout the body. The dramatic and selective loss of striatal tissue seen in HD, and the resultant pronounced behavioral and pathological effects, have remained unexplained (1, 10, 11). Given that the striatum is the predominant target of midbrain dopamine neurons, we sought to determine whether dopamine signaling might be altered in presymptomatic HD mice. We found that while many parameters of neuronal function remained unchanged, there were significant deficits including severely impaired electrophysiological and biochemical responses to activation of D1-class dopamine receptors, which precede the emergence of histopathological and behavioral changes. Materials and MethodsForskolin was purchased from LC Laboratories. 8-BromocAMP and protease type XIV were purchased from Sigma. SKF81297, D1 receptor antibodies, kainic acid, dopamine, and ␥-aminobutyric acid (GABA) were purchased from Research Biochemicals. Actin antibodies were purchased from BRL....

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Section: Discussionmentioning

confidence: 82%

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Bibb

Yan

Svenningsson

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

263

212

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“…Projection Neuron Differences-Striato-GPe and striatonigral neurons are more vulnerable in HD and ischemia than are striato-GPi neurons (Reiner et al, 1988;Albin et al, 1990aAlbin et al, ,b,1992Richfield et al, 1995;Sapp et al, 1995;Meade et al, 2000;Deng et al, 2004). The higher GluR1: GluR2 ratio in striato-GPe neurons and the greater preponderance of flip subunits in striato-GPe neurons (Tallaksen-Greene and Albin et al, 1996;Vorobjev et al, 2000) implies they have greater Ca 2+ influx and single-channel currents in response to excitatory stimulation, and are thus more likely to be damaged with overstimulation.…”

Section: Projection Neurons Versus Interneurons-thementioning

confidence: 99%

“…For example, striatal projection neurons and PARV+ interneurons are vulnerable to Huntington's disease (HD), ischemia, and/or excitotoxicity, while cholinergic, SS+, and calretinergic striatal interneurons are resistant (Dawbarn et al, 1985;Ferrante et al, 1985Ferrante et al, ,1987aBeal et al, 1986Beal et al, ,1991Kowall et al, 1987;Reiner et al, 1988;Albin et al, 1990a,b;Chesselet et al, 1990;Hawker and Lang, 1990;Uemura et al, 1990;Bazzett et al, 1993;Figueredo-Cardenas et al, 1994Richfield et al, 1995;Sapp et al, 1995;Cichetti and Parent, 1996;Cichetti et al, 1996Cichetti et al, , 2000Meade et al, 2000). Although vulnerable as a group (Vonsattel et al, 1985;Vonsattel and DiFiglia, 1998), projection neurons differ from one another in their relative vulnerability, with striato-GPi neurons being least vulnerable and striato-GPe neurons most vulnerable (Reiner et al, 1988;Albin et al, 1990a,b;Figueredo-Cardenas et al, 1994;Richfield et al, 1995;Sapp et al, 1995;Glass et al, 2000;Meade et al, 2000;Deng et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Differential localization of the GluR1 and GluR2 subunits of the AMPA-type glutamate receptor among striatal neuron types in rats

Deng

Xie

Wang

et al. 2007

Journal of Chemical Neuroanatomy

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Differences among the various striatal projection neuron and interneuron types in cortical input, function, and vulnerability to degenerative insults may be related to differences among them in AMPA-type glutamate receptor abundance and subunit configuration. We therefore used immunolabeling to assess the frequency and abundance of GluR1 and GluR2, the most common AMPA subunits in striatum, in the main striatal neuron types. All neurons projecting to the external pallidum (GPe), internal pallidum (GPi) or substantia nigra, as identified by retrograde labeling, possessed perikaryal GluR2, while GluR1 was more common in striato-GPe than striato-GPi perikarya. The frequency and intensity of immunostaining indicated the rank order of their perikaryal GluR1:GluR2 ratio to be striato-GPe > striatonigral > striato-GPi. Ultrastructural studies suggested a differential localization of GluR1 and GluR2 to striatal projection neuron dendritic spines as well, with GluR1 seemingly more common in striato-GPe spines and GluR2 more common in striato-GPi and/or striatonigral spines. Comparisons among projection neurons and interneurons revealed GluR1 to be most common and abundant in parvalbuminergic interneurons, and GluR2 most common and abundant in projection neurons, with the rank order for the GluR1:GluR2 ratio being parvalbuminergic interneurons > calretinergic interneurons > cholinergic interneurons > projection neurons > somatostatinergic interneurons. Striosomal projection neurons had a higher GluR1:GluR2 ratio than did matrix projection neurons. The abundance of both GluR1 and GluR2 in striatal parvalbuminergic interneurons and projection neurons is consistent with their prominent cortical input and susceptibility to excitotoxic insult, while differences in GluR1: GluR2 ratio among projection neurons are likely to yield differences in Ca2+ permeability, desensitization, and single channel current, which may contribute to differences among them in plasticity, synaptic integration, and excitotoxic vulnerability. The apparent association of the GluR1 subunit with synaptic plasticity, in particular, suggests striato-GPe neuron spines as a particular site of corticostriatal synaptic plasticity, presumably associated with motor learning.

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“…For example, dopamine neurons expressing the G-protein-coupled inward rectifying current potassium channel (Girk2) preferentially degenerate in patients with PD (Yamada et al, 1990;Fearnley and Lees, 1991;Gibb, 1992;Mendez et al, 2005). Enkephalin-containing GABAergic neurons projecting from the striatum to the external segment of the globus pallidus are the first to degenerate in patients with Huntington's disease (Reiner et al, 1988;Sapp et al, 1995). The fastest conducting, and presumably largest, motor neurons preferentially die in patients with amyotrophic lateral sclerosis (Theys et al, 1999).…”

Section: Implications For Cell Replacement Therapymentioning

confidence: 99%

Motoneurons Derived from Embryonic Stem Cells Express Transcription Factors and Develop Phenotypes Characteristic of Medial Motor Column Neurons

Soundararajan

Miles²,

Rubin³

et al. 2006

J. Neurosci.

101

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Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington's disease using high resolution image analysis

Cited by 147 publications

References 19 publications

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

Differential localization of the GluR1 and GluR2 subunits of the AMPA-type glutamate receptor among striatal neuron types in rats

Motoneurons Derived from Embryonic Stem Cells Express Transcription Factors and Develop Phenotypes Characteristic of Medial Motor Column Neurons

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