Glutamate-Dopamine Plasticity in Nigrostriatal Injury: Excerise Enhanced Recovery

黑质纹状体损伤中的多巴胺-谷氨酸可塑性：运动促进的恢复主要研究人员：Michael Jakowec博士和John Walsh博士。南加州大学。这项研究的主要目的是阐明多巴胺能和谷氨酸能神经传递相互作用的分子机制，以及大强度运动在神经毒物mptp(1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine).对黑质纹状体多巴胺能神经元损伤后的恢复中所起的作用。此前，在我们对MPTP损毁的小鼠多巴胺耗竭模型的研究中，我们发现高强度跑步机运动，在MPTP损毁后5天细胞完全死亡并持续28天后，改变了皮质纹状体突触的可塑性，在基底节内的多巴胺能和谷氨酸能神经传递，这些改变导致显著改善运动能力的恢复。我们发现，运动的改善不仅仅是由于通过高效液相分析测量的纹状体多巴胺总水平的变化，而是部分由于剩余黑质纹状体终末的多巴胺释放的变化，这伴随着多巴胺D2受体表达的增加。此外，对纹状体中棘神经元的分子和电生理研究表明，谷氨酸能神经传递的改变特异性地增加了谷氨酸受体AMPA亚型中的一个重要成员GluR2亚单位的表达。这项建议将利用一种名为BAC-D2-EGFP的新型转基因小鼠品系，在该品系中，绿色荧光蛋白仅在含有基底节投射神经元的间接多巴胺D2受体中表达，以确定运动诱导的变化是否具有路径特异性。小鼠将被给予MPTP或生理盐水，每组小鼠中的一组接受为期28天的高强度跑步机运动。这项提议包括两个具体目标。

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.