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 work is important because Parkinson's disease is a severely debilitating disorder afflicting over 1.5 million adults in the US and currently there is no known cure. Epidemiological and clinical studies report that exercise can influence disease prevalence and provide symptomatic benefit but the underlying mechanisms are not well understood. The purpose of this proposal is to investigate the interactions of two important neurotransmitter systems, the dopaminergic and glutamatergic, and to understand how intensive treadmill exercise in the MPTP-lesioned mouse model of basal ganglia injury can shed light on the underlying mechanism of experience-dependent neuroplasticity thus providing insights into novel therapeutic modalities.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Sieber, Beth-Anne
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University of Southern California
Schools of Medicine
Los Angeles
United States
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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
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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
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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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