Instmctions): 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

(See Instructions): 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS058830-05
Application #
8532053
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$199,983
Indirect Cost
$61,448
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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Kneynsberg, Andrew; Collier, Timothy J; Manfredsson, Fredric P et al. (2016) Quantitative and semi-quantitative measurements of axonal degeneration in tissue and primary neuron cultures. J Neurosci Methods 266:32-41
Paumier, Katrina L; Luk, Kelvin C; Manfredsson, Fredric P et al. (2015) Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185-99
Nordström, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra et al. (2015) Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease. Neurobiol Dis 73:70-82
Collier, Timothy J; O'Malley, Jennifer; Rademacher, David J et al. (2015) Interrogating the aged striatum: robust survival of grafted dopamine neurons in aging rats produces inferior behavioral recovery and evidence of impaired integration. Neurobiol Dis 77:191-203
Grabinski, Tessa M; Kneynsberg, Andrew; Manfredsson, Fredric P et al. (2015) A method for combining RNAscope in situ hybridization with immunohistochemistry in thick free-floating brain sections and primary neuronal cultures. PLoS One 10:e0120120
Polinski, Nicole K; Gombash, Sara E; Manfredsson, Fredric P et al. (2015) Recombinant adenoassociated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging 36:1110-20
Kanaan, Nicholas M; Collier, Timothy J; Cole-Strauss, Allyson et al. (2015) The longitudinal transcriptomic response of the substantia nigra to intrastriatal 6-hydroxydopamine reveals significant upregulation of regeneration-associated genes. PLoS One 10:e0127768
Fischer, D Luke; Collier, Timothy J; Cole-Strauss, Allyson et al. (2015) High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine. PLoS One 10:e0133957
Madhavan, Lalitha; Daley, Brian F; Davidson, Beverly L et al. (2015) Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration. PLoS One 10:e0137136

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