The MPTP-lesioned mouse serves as an excellent model to study the mechanisms involved in the return of striatal dopamine after basal ganglia injury. The administration of MPTP to C57BL/6 mice leads to the destruction of nigrostriatal dopaminergic neurons and subsequent depletion of striatal dopamine. An advantage of MPTP-lesioning is that the degree of neuronal cell death can be titrated such that remaining dopaminergic neurons may act as a template for repair and recovery in response to the injury. Our hypothesis is that glutamate, acting through altered expression of the AMPA-subtype of receptor, activates the transcription factor phospho-CREB and leads to increased tyrosine hydroxylase expression and axonal sprouting in surviving nigrostriatal dopaminergic neurons. This research proposal is designed to define changes that take place after MPTP injury in the expression of AMPA receptors (including their phosphorylated state), the transcription factor CREB, dopamine receptors (Dl, D2, and D3), and the growth-associated protein GAP-43. The effect of blocking glutamate neurotransmission with the AMPA receptor antagonist GYKI-52466 on these parameters will be determined. The molecular tools of immunocytochemistry, western immunoblotting, in situ hybridization, and anterograde labeling will be used to define the mechanisms involved in the return of striatal dopamine. The long-term goal of these studies is to elucidate features of plasticity following injury to the brain and to identify new therapeutic interventions for the treatment of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS044327-01
Application #
6534703
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Sheehy, Paul A
Project Start
2002-06-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$250,266
Indirect Cost
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Petzinger, G M; Holschneider, D P; Fisher, B E et al. (2015) The Effects of Exercise on Dopamine Neurotransmission in Parkinson's Disease: Targeting Neuroplasticity to Modulate Basal Ganglia Circuitry. Brain Plast 1:29-39
Toy, William A; Petzinger, Giselle M; Leyshon, Brian J et al. (2014) Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Neurobiol Dis 63:201-9
Kintz, N; Petzinger, G M; Akopian, G et al. (2013) Exercise modifies ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor expression in striatopallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse. J Neurosci Res 91:1492-507
Petzinger, Giselle M; Fisher, Beth E; McEwen, Sarah et al. (2013) Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease. Lancet Neurol 12:716-26
Petzinger, Giselle M; Fisher, Beth E; Akopian, Garnik et al. (2011) The role of exercise in facilitating basal ganglia function in Parkinson's disease. Neurodegener Dis Manag 1:157-170
Petzinger, Giselle M; Fisher, Beth E; Van Leeuwen, Jon-Eric et al. (2010) Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson's disease. Mov Disord 25 Suppl 1:S141-5
Gorton, Lori M; Vuckovic, Marta G; Vertelkina, Nina et al. (2010) Exercise effects on motor and affective behavior and catecholamine neurochemistry in the MPTP-lesioned mouse. Behav Brain Res 213:253-62
VanLeeuwen, Jon-Eric; Petzinger, Giselle M; Walsh, John P et al. (2010) Altered AMPA receptor expression with treadmill exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosci Res 88:650-68
Vu?kovi?, Marta G; Li, Quanzheng; Fisher, Beth et al. (2010) Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [ยน?F]fallypride. Mov Disord 25:2777-84
Vuckovic, Marta G; Wood, Ruth I; Holschneider, Daniel P et al. (2008) Memory, mood, dopamine, and serotonin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. Neurobiol Dis 32:319-27

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