title: Interrogating the aged striatum: robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration.
abstract: Advanced age is the primary risk factor for Parkinson's disease (PD). In PD patients and rodent models of PD, advanced age is associated with inferior symptomatic benefit following intrastriatal grafting of embryonic dopamine (DA) neurons, a pattern believed to result from decreased survival and reinnervation provided by grafted neurons in the aged host. To help understand the capacity of the aged, parkinsonian striatum to be remodeled with new DA terminals, we used a grafting model and examined whether increasing the number of grafted DA neurons in aged rats would translate to enhanced behavioral recovery. Young (3months), middle-aged (15months), and aged (22months) parkinsonian rats were grafted with proportionately increasing numbers of embryonic ventral mesencephalic (VM) cells to evaluate whether the limitations of the graft environment in subjects of advancing age can be offset by increased numbers of transplanted neurons. Despite robust survival of grafted neurons in aged rats, reinnervation of striatal neurons remained inferior and amelioration of levodopa-induced dyskinesias (LID) was delayed or absent. This study demonstrates that: 1) counter to previous evidence, under certain conditions the aged striatum can support robust survival of grafted DA neurons; and 2) unknown factors associated with the aged striatum result in inferior integration of graft and host, and continue to present obstacles to full therapeutic efficacy of DA cell-based therapy in this model of aging.
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Collier
authors.affiliation: Cincinnati Children's Hospital Medical Center, Division of Child Neurology, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Malley
authors.affiliation: Lake Forest College, Department of Psychology, 555 N Sheridan Rd, Lake Forest, IL 60045, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rademacher
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Stancati
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
authors.forename: Kellie A
authors.initials: KA
authors.lastname: Sisson
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
authors.forename: Caryl E
authors.initials: CE
authors.lastname: Sortwell
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Paumier
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.
authors.forename: Kibrom G
authors.initials: KG
authors.lastname: Gebremedhin
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine & The Udall Center of Excellence in Parkinson's Disease Research, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA. Electronic address: kathy.steece-collier@hc.msu.edu.
authors.forename: Kathy
authors.initials: K
authors.lastname: Steece-Collier
mesh_terms: D000375:Aging; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000502:physiology* / Q000601:surgery; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D004622:Embryo, Mammalian; D007839:Functional Laterality; D007980:Levodopa / Q000009:adverse effects; D016501:Neurites / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000601:surgery*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020127:Recovery of Function / Q000502:physiology*; D033581:Stem Cell Transplantation / Q000379:methods*; D013373:Substance P / Q000378:metabolism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D013373:Substance P; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine
keywords: Aging; Dyskinesias; Grafting; Levodopa; Parkinson's disease; Rodent; Synaptopodin