title: Embryonic substantia nigra grafts in the mesencephalon send neurites to the host striatum in non-human primate after overexpression of GDNF.
abstract: In spite of partial success in treating Parkinson's disease by using ectopically placed grafts of dopamine-producing cells, restoration of the original neuroanatomical circuits, if possible, might work better. Previous evidence of normal anatomic projections from ventral mesencephalic (VM) grafts placed in the substantia nigra (SN) has been limited to neonatal rodents and double grafting or bridging procedures. This study attempted to determine whether injection of a potent growth-promoting factor, glial cell line-derived neurotrophic factor (GDNF), into the target regions or placement of fetal striatal co-grafts in the nigrostriatal pathway might elicit neuritic outgrowth to the caudate nucleus. Four adult St. Kitts green monkeys received embryonic VM grafts into the rostral mesencephalon near the host SN, and injections of adeno-associated virus 2 (AAV2)/GDNF or equine infectious anemia virus (EIAV)/GDNF into the caudate. Three adult monkeys were co-grafted with fetal VM tissue near the SN and fetal striatal grafts (STR) 2.5 mm rostral in the nigrostriatal pathway. Before sacrifice, the striatal target regions were injected with the retrograde tracer Fluoro-Gold (FG). FG label was found in tyrosine hydroxylase-labeled neurons in VM grafts in the SN of only those monkeys that received AAV2/GDNF vector injections into the ipsilateral striatum. All monkeys showed FG labeling in the host SN when FG labeling was injected on the same side. These data show that grafted dopaminergic neurons can extend neurites to a distant target releasing an elevated concentration of GDNF, and suggest that grafted neurons can be placed into appropriate loci for potential tract reconstruction.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06520, USA. eugene.redmond@yale.edu
authors.forename: D E
authors.initials: DE
authors.lastname: Redmond
authors.forename: J D
authors.initials: JD
authors.lastname: Elsworth
authors.forename: R H
authors.initials: RH
authors.lastname: Roth
authors.forename: C
authors.initials: C
authors.lastname: Leranth
authors.forename: T J
authors.initials: TJ
authors.lastname: Collier
authors.forename: B
authors.initials: B
authors.lastname: Blanchard
authors.forename: K B
authors.initials: KB
authors.lastname: Bjugstad
authors.forename: R J
authors.initials: RJ
authors.lastname: Samulski
authors.forename: P
authors.initials: P
authors.lastname: Aebischer
authors.forename: J R
authors.initials: JR
authors.lastname: Sladek
mesh_terms: D000818:Animals; D016380:Brain Tissue Transplantation / Q000379:methods*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000637:transplantation*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006085:Graft Survival / Q000502:physiology; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009434:Neural Pathways / Q000166:cytology / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D013194:Staining and Labeling; D033581:Stem Cell Transplantation / Q000379:methods*; D013266:Stilbamidines; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000502:physiology
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D051100:Glial Cell Line-Derived Neurotrophic Factor; D013266:Stilbamidines