Dopamine-glutamate plasticity in nigrostriatal injury: Exercise-enhanced recovery Principal Investigators: Michael Jakowec, PhD, and John Walsh, PhD. University of Southern California. The primary goal of this research proposal is to elucidate the molecular mechanisms underlying the interactions between dopaminergic and glutamatergic neurotransmission and the role that intensive exercise plays in mediating recovery following injury to the nigrostriatal dopaminergic neurons by the neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Previously, in our studies in the MPTP-lesioned mouse model of dopamine depletion we discovered that high-intensity treadmill running, started 5 days post-MPTPlesioning when cell death is complete and continued for 28 days, altered corticostriatal synaptic plasticity in dopaminergic and glutamatergic neurotransmission within the basal ganglia and that these alterations resulted in significant improvement in the recovery of motor performance. We found that motor improvement is not simply due to changes in the total level of striatal dopamine as measured by HPLC analysis, but rather due in part to alterations in dopamine release from remaining nigrostriatal terminals, which is accompanied by increased expression of the dopamine D2 receptor. In addition, both molecular and electrophysiological studies of striatal medium spiny neurons indicated altered glutamatergic neurotransmission specifically increased expression of GluR2 subunits, an important member of the AMPA subtype of glutamate receptor. This proposal will utilize a novel transgenic mouse strain termed BAC-D2-eGFP in which green fluorescent protein is expressed exclusively within the indirect dopamine D2 receptor containing projection neurons of the basal ganglia to determine if exercise-induced changes are pathway specific. Mice will either be administered MPTP or saline and a subset from each group subjected to intensive treadmill exercise for 28 days. This proposal consists of two specific aims.

Public Health Relevance

This research proposal is part of a larger translational research program spanning basic to clinical research whose primary goal is to determine the biological mechanisms by which intensive treadmill exercise can in fact modify disease progression in basal ganglia disorders such as Parkinson's disease. Currently there are no cures for a number of important neurodegenerative disorders including Parkinson's disease. Our data demonstrates exercise, in the form of intensive treadmill running, can slow the rate of disease progression and we are confident our ongoing studies can in fact lead to important knowledge about the molecular and physiological changes, which mediate improvement in motor behavior and learning in the injured brain. Ultimately, new knowledge about these molecular and physiological pathways will help to better assess behavioral methods of intervention as well as help direct drug discovery programs in the treatment of Parkinson's disease and related movement disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS044327-05A2
Application #
7591390
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sieber, Beth-Anne
Project Start
2002-06-01
Project End
2011-05-31
Budget Start
2009-06-15
Budget End
2010-05-31
Support Year
5
Fiscal Year
2009
Total Cost
$448,250
Indirect Cost
Name
University of Southern California
Department
Neurology
Type
Schools of Medicine
DUNS #
072933393
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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