Loss of Striatal DA Innervation Increases Striatal Trophic Activity Directed at DA Neurons in Culture

Carvey, Paul M.; Lin, Donghui; Faselis, Charles; Notermann, J.K.; Ling, Zaodung

doi:10.1006/exnr.1996.0128

Cited by 35 publications

(12 citation statements)

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“…Cell survival of DA neurons is enhanced when mesencephalic neurons are co-cultured with striatal cells (Hoffman et al, 1983;Dong et al, 1993), intact or denervated striatal extracts (Dal Toso et al, 1988;Niijima et al, 1990;Carvey et al, 1996), or striatal oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells (Takeshima et al, 1994). Although this effect has been observed in vitro, it had never been documented to occur in the co-graft situation prior to our initial reports (Sortwell et al, 1996(Sortwell et al, , 1997.…”

Section: Discussionmentioning

confidence: 68%

“…Multiple influences, including extracellular matrix components and trophic factors, contribute to the establishment of this circuitry. There is abundant evidence in in vitro systems that striatal target tissue exerts both tropic and trophic effects on developing mesencephalic DA neurons (Prochiantz et al, 1979;Daguet et al, 1980;Hemmendinger et al, 1981;Hoffman et al, 1983;Tomozawa and Appel, 1986;Dal Toso et al, 1988;Niijima et al, 1990;Dong et al, 1993;Takeshima et al;, Carvey et al, 1996. Attempts have been made to extend these effects observed in culture to the mammalian brain.…”

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confidence: 97%

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Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons

1998

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To enhance the current therapeutic benefit of dopamine (DA) neuron grafts in Parkinson's disease, strategies must be developed that increase both DA neuron survival and fiber outgrowth into the denervated striatum. Previous work in our laboratory has demonstrated that dopaminergic neurons grow to greater size when co-grafted with striatal cell suspensions and display extensive tyrosine hydroxylase-positive (TH+) projections, but no conclusion could be reached concerning enhancement of survival of grafted DA neurons. The aim of the present study was to characterize further the potential trophic effects of striatal co-grafts on grafted mesencephalic DA neuron survival. Unilaterally lesioned male Fischer 344 rats were grafted with either a suspension of mesencephalic cells or with both mesencephalic and striatal cell suspensions. Co-grafts were either mixed together or placed separately into the striatum. Lesioned rats receiving no graft served as controls. Rotational behavior was assessed following amphetamine challenge at 2 weeks prior to grafting and at 4 and 8 weeks following grafting. Only rats receiving co-grafts of nigral and striatal suspensions separated by a distance of 1 mm showed significant behavioral recovery from baseline rotational asymmetry. Both mixed and separate striatal co-grafts were associated with a doubling of DA neuron survival compared with solo mesencephalic grafts. In the mixed co-graft experiment, DA neurite branching appeared enhanced and TH-rich patches were observed, whereas with co-grafts that were separated, TH+ innervation of the intervening host striatum was increased significantly. These results provide the first evidence suggesting that nigral-striatal co-grafts, particularly those placed separately and in proximity to each other, increase both DA neuron survival and neurite extension from the mesencephalic component of the grafts.

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Section: Discussionmentioning

confidence: 68%

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confidence: 97%

Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons

1998

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“…Both diffusible growthpromoting factors and membrane-or substrate-bound axon growth-regulating molecules have been implicated in this response. Studies in 6-OHDA-lesioned rats have suggested that the production of diffusible growth-stimulating factors in the striatum is increased after removal of the intrinsic DA afferents (Carvey et al, 1996) and that both BDNF and glial cell line-derived neurotrophic factor may be involved in this lesion-induced growth response (Zhou et al, 1996;Yurek and Fletcher-Turner, 2001). Signaling through membrane-bound receptor-ligand interactions between axonal growth cones and surrounding cells is also known to play a role in regulating neuronal fiber growth.…”

Section: Discussionmentioning

confidence: 99%

Identification of Dopaminergic Neurons of Nigral and Ventral Tegmental Area Subtypes in Grafts of Fetal Ventral Mesencephalon Based on Cell Morphology, Protein Expression, and Efferent Projections

Thompson¹,

Barraud²,

Andersson³

et al. 2005

J. Neurosci.

214

198

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Transplants of fetal ventral mesencephalic tissue are known to contain a mixture of two major dopamine (DA) neuron types: the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). Previous studies have suggested that these two DA neuron types may differ in their growth characteristics, but, because of technical limitations, it has so far been difficult to identify the two subtypes in fetal ventral mesencephalon (VM) grafts and trace their axonal projections. Here, we have made use of a transgenic mouse expressing green fluorescent protein (GFP) under the tyrosine hydroxylase promoter. The expression of the GFP reporter allowed for visualization of the grafted DA neurons and their axonal projections within the host brain. We show that the SNpc and VTA neuron subtypes in VM grafts can be identified on the basis of their morphology and location within the graft, and their expression of a G-protein-gated inwardly rectifying K ϩ channel subunit (Girk2) and calbindin, respectively, and also that the axonal projections of the two DA neuron types are markedly different. By retrograde axonal tracing, we show that dopaminergic innervation of the striatum is derived almost exclusively from the Girk2-positive SNpc cells, whereas the calbindin-positive VTA neurons project to the frontal cortex and probably also other forebrain areas. The results suggest the presence of axon guidance and target recognition mechanisms in the DA-denervated forebrain that can guide the growing axons to their appropriate targets and indicate that cell preparations used for cell replacement in Parkinson's disease will be therapeutically useful only if they contain cells capable of generating the correct nigral DA neuron phenotype.

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“…Both cell-specific recognition molecules and diffusible growthstimulating factors may be involved in this effect. Carvey et al (1989Carvey et al ( , 1996 have shown that adult striatal tissue contains a neurotrophic activity (active on DA neurons in culture) that is increased after lesion of the nigrostriatal afferents or blockade of DA receptors. The factor or factors involved have so far not been identified, but several growth factors with neurotrophic activity on DA neurons are known to be expressed at elevated levels in the DA-denervated striatum (Funa et al, 1996;Zhou et al, 1996; Figure 7.…”

Section: Discussionmentioning

confidence: 99%

Growth and Functional Efficacy of Intrastriatal Nigral Transplants Depend on the Extent of Nigrostriatal Degeneration

2001

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Previous studies have shown that the functional efficacy of intrastriatal transplants of fetal dopamine (DA) neurons in the rat Parkinson model depends on their ability to establish a new functional innervation of the denervated striatum. Here we report that the survival, growth, and function of the grafted DA neurons greatly depend on the severity of the lesion of the host nigrostriatal system. Fiber outgrowth, and to a lesser extent also cell survival, were significantly reduced in animals in which part of the intrinsic DA system was left intact. Moreover, graftinduced functional recovery, as assessed in the stepping, pawuse, and apomorphine rotation tests, was obtained only in severely lesioned animals, i.e., in rats with Ͼ70% DA denervation of the host striatum. Functional recovery seen in these animals in which the 6-hydroxydopamine (6-OHDA) lesion was confined to the striatum was more pronounced than that previously obtained in rats with complete lesions of the mesencephalic DA system, indicating that spared portions of the host DA system, particularly those innervating nonstriatal forebrain areas, may be necessary for the grafts to exert their optimal functional effect. These data have implications for the optimal use of fetal nigral transplants in Parkinson patients in different stages of the disease.Key words: Parkinson's disease; transplantation; sensorimotor behavior; stepping; paw use; tyrosine hydroxylase; stereology Impairments in sensorimotor function induced by lesions of the nigrostriatal DA system can be reversed by intrastriatal transplants of nigral DA neurons taken from the fetal ventral mesencephalon (VM). However, functional recovery is incomplete: whereas some aspects of the DA deficiency syndrome are completely reversed (e.g., drug-induced turning behavior and sensorimotor neglect), other deficits, such as forelimb akinesia and skilled paw-use, are only partly or marginally affected by the grafted DA neurons (Björklund et al., 1994;Herman and Abrous, 1994;Winkler et al., 1999). The functional capacity of intrastriatal VM transplants is determined, at least in part, by the extent of striatal reinnervation provided by the grafted DA neurons and the placement of the cells, i.e., the subregion of the striatal complex reached by the graft-derived axons Mandel et al., 1990;Annett et al., 1995). Nevertheless, attempts to improve the functional efficacy of intrastriatal nigral transplants by multiple graft placements have so far been unsuccessful (Nikkhah et al., 1993;Olsson et al., 1995;Winkler et al., 1999). In these experiments the entire caudate putamen was reinnervated to a level of ϳ30 -80% of normal, but recovery of forelimb akinesia and paw use remained incomplete. These studies, however, were performed in rats with a complete unilateral 6-OHDAinduced lesion of the medial forebrain bundle (MFB), resulting in a widespread denervation of both striatal, limbic, and cortical areas. The functional impairments seen in these animals, therefore, reflect a combination of striatal and nonstria...

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Loss of Striatal DA Innervation Increases Striatal Trophic Activity Directed at DA Neurons in Culture

Cited by 35 publications

References 0 publications

Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons

Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons

Identification of Dopaminergic Neurons of Nigral and Ventral Tegmental Area Subtypes in Grafts of Fetal Ventral Mesencephalon Based on Cell Morphology, Protein Expression, and Efferent Projections

Growth and Functional Efficacy of Intrastriatal Nigral Transplants Depend on the Extent of Nigrostriatal Degeneration

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