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：多巴胺增强恢复主要研究者：Michael Jakowec博士和John沃尔什博士。南加州大学。本研究的主要目的是阐明多巴胺能和多巴胺能神经传递之间相互作用的分子机制，以及剧烈运动在神经毒物MPTP（1-甲基-4-苯基-1，2，3，6-四氢吡啶）损伤黑质纹状体多巴胺能神经元后介导恢复中的作用。以前，在我们对MPTP损伤的多巴胺耗竭小鼠模型的研究中，我们发现，在MPTP损伤后5天细胞完全死亡时开始高强度跑步机跑步并持续28天，改变了基底神经节内多巴胺能和多巴胺能神经传递的皮质纹状体突触可塑性，并且这些改变导致运动性能恢复的显著改善。我们发现，运动的改善是不是简单地由于纹状体多巴胺的总水平的变化，通过HPLC分析测量，而是部分由于从剩余的黑质纹状体终端，这是伴随着多巴胺D2受体的表达增加的多巴胺释放的改变。此外，纹状体中棘神经元的分子和电生理研究表明，改变的谷氨酸能神经传递特异性增加GluR 2亚单位的表达，谷氨酸受体的AMPA亚型的重要成员。该提议将利用一种称为BAC-D2-eGFP的新型转基因小鼠品系，其中绿色荧光蛋白仅在含有基底神经节投射神经元的间接多巴胺D2受体内表达，以确定运动诱导的变化是否是通路特异性的。小鼠将被施用MPTP或盐水，并且来自每组的一个亚组经受28天的密集跑步机运动。这项建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.