Anatomical and functional reconstruction of the nigrostriatal pathway by intranigral transplants.
The main transplantation strategy in Parkinson's disease has been to place dopaminergic grafts not in their ontogenic site, the substantia nigra, but in their target area, the striatum with contrasting results. Here we have used green fluorescent protein transgenic mouse embryos as donors of ventral mesencephalic cells for transplantation into the pre-lesioned substantia nigra of an adult wild-type host. This allows distinguishing the transplanted cells and their projections from those of the host. Grafted cells integrated within the host mesencephalon and expressed the dopaminergic markers tyrosine hydroxylase, vesicular monoamine transporter 2 and dopamine transporter. Most of the dopaminergic cells within the transplant expressed the substantia nigra marker Girk2 while a lesser proportion expressed the ventral tegmental area marker calbindin. Mesencephalic transplants developed projections through the medial forebrain bundle to the striatum, increased striatal dopamine levels and restored normal behavior. Interestingly, only mesencephalic transplants were able to restore the nigrostriatal projections as dopamine neurons originating from embryonic olfactory bulb transplants send projections only in the close vicinity of the transplantation site that did not reach the striatum. Our results show for the first time the ability of intranigral foetal dopaminergic neurons grafts to restore the damaged nigrostriatal pathway in adult mice. Together with our previous findings of efficient embryonic transplantation within the pre-lesioned adult motor cortex, these results demonstrate that the adult brain is permissive to specific and long distance axonal growth. They further open new avenues in cell transplantation therapies applied for the treatment of neurodegenerative disorders such as Parkinson's disease.
Gaillard
Afsaneh
A
Institut de Physiologie et de Biologie Cellulaires, University of Poitiers, CNRS, 40 avenue recteur Pineau, 86022 Poitiers Cedex, France. Afsaneh.Gaillard@univ-poitiers.fr
Decressac
Mickael
M
Frappé
Isabelle
I
Fernagut
Pierre Olivier
PO
Prestoz
Laetitia
L
Besnard
Stephan
S
Jaber
Mohamed
M
D000375:Aging; D000818:Animals; D016380:Brain Tissue Transplantation; D064026:Calbindins; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D016332:Fetal Tissue Transplantation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D008636:Mesencephalon / Q000196:embryology* / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009830:Olfactory Bulb / Q000196:embryology / Q000637:transplantation; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D064026:Calbindins; D050483:Dopamine Plasma Membrane Transport Proteins; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D064030:S100 Calcium Binding Protein G; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine