Parkinsonian Motor Deficits Are Reflected by Proportional A9/A10 Dopamine Neuron Degeneration in the Rat

Moore, Allan F.; Cicchetti, Francesca; Hennen, John; Isacson, Ole

doi:10.1006/exnr.2001.7823

Cited by 28 publications

(14 citation statements)

References 47 publications

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“…Parkinson’s disease is typically attributed to SNc MbDA neuron loss (Parent, 1996), but is often accompanied by VTA loss (Damier et al, 1999; Hirsch et al, 1988; Uhl et al, 1985). Additionally, movement deficits in Parkinsonian animal models either worsen or unique deficits appear when VTA DA neurons are compromised (Heim et al, 2002; Moore et al, 2001). This is likely because of the VTA involvement in planning, initiation, and motivation of movement (Uhl et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of midbrain dopamine neuron development in vivo

Ellisor¹,

Rieser²,

Voelcker³

et al. 2012

Developmental Biology

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Midbrain dopamine (MbDA) neurons are partitioned into medial and lateral cohorts that control complex functions. However, the genetic underpinnings of MbDA neuron heterogeneity are unclear. While it is known that Wnt1-expressing progenitors contribute to MbDA neurons, the role of Wnt1 in MbDA neuron development in vivo is unresolved. We show that mice with a spontaneous point mutation in Wnt1 have a unique phenotype characterized by the loss of medial MbDA neurons concomitant with a severe depletion of Wnt1-expressing progenitors and diminished LMX1a-expressing progenitors. Wnt1 mutant embryos also have alterations in a hierarchical gene regulatory loop suggesting multiple gene involvement in the Wnt1 mutant MbDA neuron phenotype. To investigate this possibility, we conditionally deleted Gbx2, Fgf8, and En1/2 after their early role in patterning and asked whether these genetic manipulations phenocopied the depletion of MbDA neurons in Wnt1 mutants. The conditional deletion of Gbx2 did not result in re-positioning or distribution of MbDA neurons. The temporal deletion of Fgf8 did not result in the loss of either LMX1a-expressing progenitors nor the initial population of differentiated MbDA neurons, but did result in a complete loss of MbDA neurons at later stages. The temporal deletion and species specific manipulation of En1/2 demonstrated a continued and species specific role of Engrailed genes in MbDA neuron development. Notably, our conditional deletion experiments revealed phenotypes dissimilar to Wnt1 mutants indicating the unique role of Wnt1 in MbDA neuron development. By placing Wnt1, Fgf8, and En1/2 in the context of their temporal requirement for MbDA neuron development, we further deciphered the developmental program underpinning MbDA neuron progenitors.

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Section: Discussionmentioning

confidence: 99%

Genetic dissection of midbrain dopamine neuron development in vivo

Ellisor¹,

Rieser²,

Voelcker³

et al. 2012

Developmental Biology

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“…We used the D2-receptor agonist apomorphine, which causes contralateral rotations, as a way to determine completeness of the 6-OHDA-lesions in living animals, as it is difficult to determine the completeness of a striatal dopaminergic deafferentiation by amphetamine (Hefti et al 1980;Heikkila et al 1981;Casas et al 1988;Carman et al 1991;Hudson et al 1993;Moore et al 2001). Apomorphine-induced rotations (Teclapharm, 0.25 mg kg -1 s.c.) were monitored over 40 min, 12 days after lesion and regularly for 12 weeks after transplantation using an automated rotometer system according to Ungerstedt & Arbuthnott (1970).…”

Section: Apomorphine-induced Rotations and Statisticsmentioning

confidence: 99%

Orthotopic transplantation of immortalized mesencephalic progenitors (CSM14.1 cells) into the substantia nigra of hemiparkinsonian rats induces neuronal differentiation and motoric improvement

et al. 2007

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Neural progenitor cell grafting is a promising therapeutic option in the treatment of Parkinson's disease. In previous experiments we grafted temperature-sensitive immortalized CSM14.1 cells, derived from the ventral mesencephalon of E14-rats, bilaterally in the caudate putamen of adult hemiparkinsonian rats. In these studies we were not able to demonstrate either a therapeutic improvement or neuronal differentiation of transplanted cells. Here we examined whether CSM14.1 cells grafted bilaterally orthotopically in the substantia nigra of hemiparkinsonian rats have the potential to differentiate into dopaminergic neurons. Adult male rats received 6-hydroxydopamine into the right medial forebrain bundle, and successful lesions were evaluated with apomorphine-induced rotations 12 days after surgery. Two weeks after a successful lesion the animals received bilateral intranigral grafts consisting of either about 50 000 PKH26-labelled undifferentiated CSM14.1 cells ( n = 16) or a sham-graft ( n = 9). Rotations were evaluated 3, 6, 9 and 12 weeks post-grafting. Animals were finally perfused with 4% paraformaldehyde. Cryoprotected brain slices were prepared for immunohistochemistry using the freeze-thaw technique to preserve PKH26-labelling. Slices were immunostained against neuronal epitopes (NeuN, tyrosine hydroxylase) or glial fibrillary acidic protein. The CSM14.1-cell grafts significantly reduced the apomorphine-induced rotations 12 weeks post-grafting compared to the sham-grafts ( P < 0.05). There was an extensive mediolateral migration (400-700 µ m) of the PKH26-labelled cells within the host substantia nigra. Colocalization with NeuN or glial fibrillary acidic protein in transplanted cells was confirmed with confocal microscopy. No tyrosine hydroxylase-immunoreactive grafted cells were detectable. The therapeutic effect of the CSM14.1 cells could be explained either by their glial cell-derived neurotrophic factor-expression or their neural differentiation with positive effects on the basal ganglia neuronal networks.

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“…8a). To test whether intrastriatal TGF␣ administration can restore motor function to rats with a unilateral 6-OHDA lesion, amphetamine rotations were used before infusion and after 4 weeks of infusion (Moore et al, 2001). No significant reductions in rotation scores were recorded using this behavioral test (Fig.…”

Section: Differentiation Of Nestin؉ Progenitorsmentioning

confidence: 99%

Intrastriatal Transforming Growth Factor α Delivery to a Model of Parkinson's Disease Induces Proliferation and Migration of Endogenous Adult Neural Progenitor Cells without Differentiation into Dopaminergic Neurons

Cooper

Isacson²

2004

J. Neurosci.

150

111

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We examined the cell proliferative, neurogenic, and behavioral effects of transforming growth factor ␣ (TGF␣) in a 6-OHDA Parkinson's disease model when compared with naive rats. Intrastriatal TGF␣ infusion induced significant proliferation, hyperplastic nodules, and substantial migratory waves of nestin-positive progenitor cells from the adult subventricular zone (SVZ) of dopamine-denervated rats. Interestingly, SVZ cells in naive rats displayed proliferation but minimal migration in response to the TGF␣ infusion. The cells in the expanded SVZ accumulated cytoplasmic ␤-catenin, indicating activation of classical Wnt signaling. However, no evidence of any neuronal differentiation was found of these recruited progenitor cells anywhere examined in the brain. Consequently, no evidence of dopaminergic (DA) neurogenesis was found in the striatum or substantia nigra in any experimental group, and amphetamine-induced behavioral rotations did not improve. In summary, the cells in the TGF␣-induced migratory cellular wave remain undifferentiated and do not differentiate into midbrain-like DA neurons.

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Parkinsonian Motor Deficits Are Reflected by Proportional A9/A10 Dopamine Neuron Degeneration in the Rat

Cited by 28 publications

References 47 publications

Genetic dissection of midbrain dopamine neuron development in vivo

Genetic dissection of midbrain dopamine neuron development in vivo

Orthotopic transplantation of immortalized mesencephalic progenitors (CSM14.1 cells) into the substantia nigra of hemiparkinsonian rats induces neuronal differentiation and motoric improvement

Intrastriatal Transforming Growth Factor α Delivery to a Model of Parkinson's Disease Induces Proliferation and Migration of Endogenous Adult Neural Progenitor Cells without Differentiation into Dopaminergic Neurons

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