Aging and Parkinson's disease: Models of therapeutics and neurologic comorbidity. This is an A2 application for a Udall Parkinson's Disease Center of Excellence from the University of Cincinnati directed by Timothy J. Collier, Ph.D. Two less studied aspects of Parkinson's disease (PD) are the neural mechanisms associated with development of adverse consequences of disease and treatment (such as depression and therapy-induced dyskinesias) and mechanisms associated with translational therapeutics (such as subthalamic nucleus DBS and progenitor ceU transplantation). In addition, it long has been appreciated that advancing age is a primary risk factor for PD, yet aging rarely is incorporated into experimental studies. Thus, the present proposal groups these topics under the rubric of "adaptive and maladaptive plasticity"and examines their expression in the context of advancing chronological age. The proposal consists of four projects and two cores that interconnect and serve the projects. Project 1 examines the roles of maladaptive changes in spine morphology in suboptimal recovery provided by grafted dopamine (DA) neurons and the development of therapy-induced dyskinesias. Project 2 will determine the degree and mechanism of neuroprotection for the DA system conferred by high frequency electrical stimulation of the subthalamic nucleus. In particular, stimulation effects on neurotrophic mechanisms wUl be examined. Project 3 tests the hypothesis that preservation of the structure and function of the injured nigrostriatal system following engraftment of undifferentiated neural progenitor ceUs is not a product of replacement of DA neurons by grafted cells, but is mediated by graft-induced protection and/or regeneration of mature host DA neurons. The goal of Project 4 is to gain insight into the co-mingling of PD, stress, anxiety and depression. It will test the hypothesis that comorbid depression exacerbates the behavioral deficits, neurochemical abnormalities, and neurodegeneration associated with PD via deleterious glucocorticoid mechanisms. AH projects will utilize well-established rat models and examine differences and similarities of mechanisms and outcomes in the context of advancing chronological age. To the extent that plasticity is characteristic of PD, it provides points of access to harness its therapeutic effects and curtail its negative effects. PUBLIC HEALTH RELEVANCE: The proposed program will provide important insights leading the optimization of pharmacological, ceil transplant, and deep brain stimulation therapies for Parkinson's disease. PROJECT 1 Principal Investigator: Kathy Steece-Collier, Ph.D. Title: Profiles of Maladaptive Plasticity: Impact on Graft and Levodopa Efficacy Description (provided by applicant): Grafting of dopamine (DA) neurons provides benefit in some individuals with Parkinson's disease (PD), however, overall efficacy is less than would be predicted from the degree of DA replacement provided in many individuals. Similarly, while DA grafts in parkinsonian rats can completely reverse amphetamine-induced rotations, more complex motor behaviors often show little to no improvement. Many issues thought to underlie lack of graft success in PD are being investigated. Primary among these is low cell survival following grafting into the aged, parkinsonian brain. However, we hypothesize that there are critical factors not yet considered that contribute to the overall lack of graft success. Specifically, the primary site for afferent input of nigral DA and cortical glutamate neurons are medium spiny neurons (MSNs) within striatum. The numerous dendritic "spines" found on normal MSNs are critical sites of synaptic integration for DA and glutamate signaling. In advanced PD there is a marked atrophy of dendrites and spines on MSNs (McNeill, 1988;Zaja-Milatovic, 2005;Stephens, 2005). The premise of this project is that these severe morphological alterations will have grave consequences for cell replacement therapies despite the number of cells grafted. Pathological alterations of neuron structure would also be expected to negatively impact traditional dopamine replacement pharmacotherapies. Similar to PD, mice and rats with severe DA depletion also show significant decrease in spine density on MSNs. Importantly, a new mechanism involving dysregulation of intraspine Cavl.3 Ca2+ channels has been found to account for this spine loss. Indeed, absence of Cavl.3 channels in transgenic mice or administration of the Cavl.3 antagonist nimodipine to 6-OHDA lesioned rats can prevent spine loss in the presence of severe striatal DA depletion (Day, 2006). Identification of this mechanism allows testing the hypotheses put forth in this project: 1) degenerative changes in spine density of MSN has a detrimental impact on DA graft efficacy;2) altered spine morphology plays a role in the development of levodopa-induced and/or DA graft-induced dyskinetic behaviors. The proposed studies will employ the well-established rat model of parkinsonism and dyskinesia. Using light and electron microscopic analyses and multiple behavioral profiles, we will compare therapeutic benefit and/or development of abnormal behaviors between DA-depleted rats with normal spine morphology to those with significant spine atrophy. We will further investigate how the risk factor of advanced age may impact potential dendritic spine regeneration. Public Health Relevance: Project 1 will provide novel insight into the role of striatal pathology, specifically loss of dendritic spines on medium spiny output neurons, on dopamine replacement therapy. These studies may allow for improved treatment efficacy for patients with Parkinson's disease.
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NIH ExPorter