An immunohistochemical investigation of the human neostriatum in huntington's disease

Goto, Satoshi; Hirano, Atsushi; Rojas–Corona, R. R.

doi:10.1002/ana.410250315

Cited by 62 publications

(45 citation statements)

References 32 publications

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“…The observed reduction in huntingtin phosphorylation could result from a reduction in Akt activity (Colin et al, 2005) but also from an excess of calcineurin phosphatase activity. Indeed, calcineurin phosphatase is highly expressed in the striatum and in particular in the medium-size spiny neurons (MSNs), the first cells to degenerate in HD (Goto et al, 1989), and could therefore predispose huntingtin to dephosphorylation in these cells. Calcineurin is activated by Ca 2ϩ (Mansuy, 2003), and several studies indicate that excessive Ca 2ϩ entry in striatal neurons could play a role in HD (Bezprozvanny and Hayden, 2004).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

et al. 2006

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Section: Discussionmentioning

confidence: 99%

Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

et al. 2006

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“…Medium-sized spiny striatal neurons, and those neurochemical substances contained within them, are disproportionately affected early and most severely in HD (Marshall et al, 1983;Graveland et al, 1985;Ferrante et al, 1986Ferrante et al, , 1991Seto-Oshima et al, 1988;Goto et al, 1989), whereas large and medium-sized aspiny striatal neurons and their chemical components are relatively spared (Dawbarn et al, 1985;Ferrante et al, , 1987aAlbin et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Topographic and Cellular Distribution of Huntingtin Expression in the Normal Human Neostriatum

et al. 1997

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A striking heterogeneous distribution of topographic and cellular huntingtin immunoreactivity was observed within the human neostriatum using three distinct huntingtin antibodies. Patchy areas of low huntingtin immunoreactivity were present in both the caudate nucleus and putamen, surrounded by an intervening area of greater immunoreactivity. Comparison of huntingtin immunoreactivity with contiguous serial sections stained for enkephalin and calbindin D28k immunoreactivities showed that the topographic heterogeneity of huntingtin immunostaining corresponded to the patch (striosome) and matrix compartments within the striatum. Huntingtin immunoreactivity was confined primarily to neurons and neuropil within the matrix compartment, whereas little or no neuronal or neuropil huntingtin immunostaining was observed within the patch compartment. There was marked variability in the intensity of huntingtin immunolabel among medium-sized striatal neurons, whereas a majority of large striatal neurons were only faintly positive or without any immunoreactivity. Combined techniques for NADPH-diaphorase enzyme histochemistry and huntingtin immunocytochemistry, as well as double immunofluorescence for either nitric oxide synthase or calbindin D28k in comparison with huntingtin expression, revealed a striking correspondence between calbindin D28k and huntingtin immunoreactivities, with little or no colocalization between NADPH-diaphorase or nitric oxide synthase neurons and huntingtin expression. These observations suggest that the selective vulnerability of spiny striatal neurons and the matrix compartment observed in Huntington's disease is associated with higher levels of huntingtin expression, whereas the relative resistance of large and medium-sized aspiny neurons and the patch compartments to degeneration is associated with low levels of huntingtin expression.

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“…Excitotoxic processes preferentially affecting one EAA receptor subtype would give rise to discrete striatal pathology. The phenomenon of compartment-specific abnormalities has been postulated to contribute to the pathophysiology of Huntington disease (80)(81)(82). It has been demonstrated that enkephalinergic striatal projections to the GPe are affected early in the disease (61).…”

Section: Discussionmentioning

confidence: 99%

Compartmentalization of excitatory amino acid receptors in human striatum.

Dure

Young

Penney

1992

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

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Division of the mammalian neostriatum into two intermingled compartments called striosomes and matrix has been established by analysis of enzyme activity, neuropeptide distribution, nucleic acid hybridization, and neurotransmitter receptor binding. Striosomes and matrix are distinct with respect to afferent and efferent connections, and these regions provide the potential for modulation and integration of information flow within basal ganglia circuitry. The primary neurotransmitters of corticostriatal afferents are excitatory amino acids, but to date no correlation of excitatory amino acid receptors and striatal compartments has been described. We examined binding to the three pharmacologically distinct ionotropic excitatory amino acid receptors, N-methyl-D-aspartate, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and kainate, in human striatum using in vitro receptor autoradiography and compared the binding to striosomes and matrix histochemically dermed by acetylcholinesterase activity. Our findings reveal increased binding to N-methyl-D-aspartate receptors and a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in matrix relative to striosomes and increased kainate receptor binding in striosomes relative to matrix. These results suggest that afferent input to the two striatal compartments may be mediated by pharmacoloically distinct excitatory amino acid receptor subtypes.The mammalian neostriatum, composed of the caudate nucleus and putamen, participates in the modulation ofneuronal activity associated with cognitive, affective, and performance aspects of motor function. Abundant corticostriatal afferents from frontal, limbic, and primary sensorimotor cortex subserve these distinct but interrelated functions. Striatal efferents projecting to globus pallidus (GP) and substantia nigra (SN) integrate and modulate motor activities via direct and indirect pallidal motor circuits that ultimately project back to cerebral cortex. Recent evidence suggests that the neostriatum is able to maintain segregated information flow due to compartmentalization in mammalian caudate and putamen (1-11). Distinct regions within caudate and putamen have been defined in several species with histochemical techniques, in situ hybridization, and neurotransmitter receptor binding studies in rat (1,(12)(13)(14)(15), cat (10, 14, 16-20), primate (12, 14, 19-22), and human (20,(23)(24)(25)(26). These compartments, termed striosomes and matrix, exhibit distinct afferent and efferent connections. In rat, cat, and primate, striosomes receive input primarily from prefrontal cortex, insular cortex, and amygdala, whereas the major projection to matrix is from association and sensorimotor cortex (2,27,28). Within the feline and rat neostriatum, interneurons may function to allow striosomal/matrix interactions (29-31).Separate striatal circuitry is preserved for efferent connections of striatum, with striosomal neurons projecting mainly to the substantia nigra pars compacta (SNc) and the majority of matrix neurons projec...

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An immunohistochemical investigation of the human neostriatum in huntington's disease

Cited by 62 publications

References 32 publications

Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

Heterogeneous Topographic and Cellular Distribution of Huntingtin Expression in the Normal Human Neostriatum

Compartmentalization of excitatory amino acid receptors in human striatum.

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