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.
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.
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