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Differential Involvement of Striosome and Matrix Dopamine Systems in a Transgenic Model of Dopa-Responsive Dystonia

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Differential Involvement of Striosome and Matrix Dopamine Systems in a Transgenic Model of Dopa-Responsive Dystonia Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia Kenta Sato*†, Chiho Sumi-Ichinose†‡, Ryuji Kaji*, Kazuhisa Ikemoto‡, Takahide Nomura‡, Ikuko Nagatsu§, Hiroshi Ichinose¶, Masayuki Ito‡, Wataru Sako*, Shinji Nagahiroʈ, Ann M. Graybiel**††, and Satoshi Goto*†† *Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima 770-8503, Japan; ‡Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan; §Department of Anatomy, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan; ¶Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan; ʈDepartment of Neurosurgery, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, Tokushima 770-8503, Japan; and **McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 Contributed by Ann M. Graybiel, July 1, 2008 (sent for review February 1, 2008) Dopa-responsive dystonia (DRD) is a hereditary dystonia character- DRD (9). Some parkinsonian symptoms are present in DRD, ized by a childhood onset of fixed dystonic posture with a dramatic especially with increasing age, but dystonia is predominant. and sustained response to relatively low doses of levodopa. DRD is DRD thus presents critical questions about how striatal dopa- thought to result from striatal dopamine deficiency due to a reduced mine affects motor behavior: why a striatal dopamine deficiency synthesis and activity of tyrosine hydroxylase (TH), the synthetic leads mainly to dystonia rather than to parkinsonism in DRD, enzyme for dopamine. The mechanisms underlying the genesis of and why levodopa treatment so effectively treats the dystonia dystonia in DRD present a challenge to models of basal ganglia (6, 7, 10, 11). movement control, given that striatal dopamine deficiency is the To address these issues, Sumi-Ichinose et al. (12) generated a hallmark of Parkinson’s disease. We report here behavioral and mouse model of autosomal dominant DRD (the PtsϪ/Ϫ mouse) anatomical observations on a transgenic mouse model for DRD in by disrupting the synthesis of BH4 through disabling of the PTS NEUROSCIENCE which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted gene, necessary for BH4 synthesis (12). Because PtsϪ/Ϫ mice died to render selective dysfunction of TH synthesis in the striatum. shortly after birth, a rescue DRD model was generated by Mutant mice exhibited motor deficits phenotypically resembling transgenic introduction of human PTS cDNA under the control symptoms of human DRD and manifested a major depletion of TH of the 5Ј-promoter region of the human dopamine ␤-hydroxylase labeling in the striatum, with a marked posterior-to-anterior gradient (DBH: EC1.14.17.1) gene (13). In these DPS-rescued PtsϪ/Ϫ resulting in near total loss caudally. Strikingly, within the regions of mice (DPS mice), BH4 and TH concentrations are severely remaining TH staining in the striatum, there was a greater loss of TH reduced in the striatum (to Ϸ20% and 15%, respectively, of labeling in striosomes than in the surrounding matrix. The predom- wild-type Ptsϩ/ϩ levels), but noradrenaline and adrenaline are inant loss of TH expression in striosomes occurred during the early largely spared (13). postnatal period, when motor symptoms first appeared. We suggest In the experiments reported here, we show that DPS mice that the differential striosome-matrix pattern of dopamine loss could develop abnormal postures and movements, and that the devel- be a key to identifying the mechanisms underlying the genesis of opment of such symptoms is correlated temporally with highly dystonia in DRD. patterned loss of TH in the striatum involving both a loss of TH in striosomes and a failure of increase of TH in both striosomes basal ganglia ͉ movement disorders ͉ Parkinson’s disease ͉ striatum and matrix. We suggest that differential loss of dopamine in striosomes, together with a more global dopaminergic deficit in arkinson’s disease (PD), Huntington’s disease, and the dys- the striatum, may be critical in producing dystonia in DRD. tonias represent the three main classes of basal ganglia P Results disorders producing severe motor disturbances. Dystonias, the most common of these, are characterized by the occurrence of Motor Dysfunction in DPS Mice. To determine whether the DPS sustained muscle contractions and cocontractions leading to mice had motor impairments, we evaluated mutants along with repetitive patterned movements (hyperkinetic dystonias) or sibling controls in a series of behavior tests. At rest, adult DPS fixed abnormal postures (hypokinetic dystonias). Many forms of mice demonstrated no overt signs of movement disorder. How- dystonia now are recognized as genetic disorders, classified as ever, when hung by their tails, the DPS mice exhibited dystonic DYT-1 to DYT-16 (1–4). posture of the hindlimbs with self-clasping (Fig. 1, also see Movie Dopa-responsive dystonia (DRD), a hypokinetic dystonia, was S1). The fixed clasping posture was first detected in young DPS the first dystonic syndrome for which a causative gene was mice at 2 weeks of age (Fig. 1C). We tested mature DPS mice and identified (GCH1) (5). DRD is remarkable among dystonias, sibling controls with beam-walking protocols including three because it is highly responsive to treatment with levodopa, the signature treatment for PD. Autosomal dominant DRD mani- Author contributions: A.M.G. and S.G. designed research; K.S., C.S.-I., K.I., M.I., and W.S. fested by fixed dystonic postures can result from all of the performed research; I.N., H.I., and S.N. contributed new reagents/analytic tools; K.S., C.S.-I., inherited metabolic disorders involving synthesis of BH4 (L- R.K., T.N., A.M.G., and S.G. analyzed data; and A.M.G. and S.G. wrote the paper. erythro-5,6,7,8-tetrahydrobiopterin), because this enzyme is the The authors declare no conflict of interest. essential cofactor for tyrosine hydroxylase (TH: EC1.14.16.3), †K.S. and C.S.-I. contributed equally to this work. itself the critical enzyme for synthesizing dopamine and other ††To whom correspondence may be addressed. E-mail: [email protected] or monoamines [supporting information (SI) Fig. S1] (5–8). Loss of [email protected]. dopamine in the striatum, together with reduced striatal TH This article contains supporting information online at www.pnas.org/cgi/content/full/ activity and TH protein, are the key features that have been 0806065105/DCSupplemental. observed in the rare autopsied cases of autosomal dominant © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806065105 PNAS ͉ August 26, 2008 ͉ vol. 105 ͉ no. 34 ͉ 12551–12556 Downloaded by guest on September 30, 2021 15 E * ABCP CP A B * 10 * 5 mean latency (sec) 0 6Sq 14R 8R C D F 15 * 10 NA NA 5 * * OT OT mean latency (sec) 0 6Sq 14R 8R CD Fig. 1. Behavioral phenotype of DPS mice. (A–D) Hindlimb clasping dystonic phenotype in DPS mice (A and C) compared with behavior in wild-type sibling controls (B and D), at adulthood (A and B), and at 2 wk of age (C and D). Note * normal splaying of hindlimbs in wild type. (E and F) Hypokinetic motor deficits * in adult DPS mice. On the beam-walking tests with a 6-mm-wide square beam (6Sq) and with 14 mm (14R)- or 8 mm (8R)-wide round beams, DPS mice (black bars) showed an increase in the latency to complete crossing (E) and in the number of foot slips (F), relative to controls. *, P ϭ 0.001. beams of different shapes and diameters. The DPS mice were EGF impaired relative to wild-type controls on all tests. DPS mice were slower (Fig. 1E, latency to complete crossing; P ϭ 0.001, M S ANOVA) and made more foot slips (Fig. 1F; P ϭ 0.001, ANOVA) (see Movie S2). These results suggest that DPS mice S manifest a phenotype of hypokinetic hindlimb dystonia that resembles the hindlimb dystonia observed in DRD, including in a patient with a PTS deficiency (8), specifically modeled genet- Fig. 2. Differential loss of TH labeling in striosomes in adult DPS mice. (A and B) TH-stained cross-sections through the striatum from a wild-type mouse (A) ically in the DPS mice. and a DPS mouse (B). An example of the focal zones of lowered TH-staining visible in the DPS mouse is indicated by the arrow in B.(C and D) Serially Patterns of Loss of TH Immunostaining in the Striatum of Adult DPS adjacent striatal sections immunostained for TH (C) and for MOR (D) from a Mice. Immunohistochemistry for TH demonstrated striking ab- DPS mouse. * indicates examples of MOR-positive striosomes that correspond normalities in the striatum of the adult DPS mice (Fig. 2). In to the TH-poor zones. (E) Photomicrograph illustrating magnified view of contrast to the intense, nearly homogeneous TH staining in the TH-immunostaining in caudoputamen of a DPS mouse. Striosome and matrix striatum of wild-type controls, striatal TH immunostaining in compartments are indicated by S and M, respectively. (F and G) Higher-power the DPS mice was markedly reduced in the caudoputamen and photomicrographs showing a severe loss of TH-immunostained afferent fibers in the lateral part of the olfactory tubercle, but not in the nucleus in a striosome (F), but their relative sparing in the nearby matrix (G)inthe caudoputamen of a DPS mouse. (Scale bars: A–D, 500 ␮m; E, 200 ␮m; and F and accumbens (Fig. 2B). Within the caudoputamen of the DPS G,50␮m.) CP, caudoputamen; NA, nucleus accumbens; OT, olfactory tubercle.
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