Farrand Ariana Q, Gregory Rebecca A, Scofield Michael D, Helke Kristi L, Boger Heather A
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC, USA.
Neurobiol Aging. 2015 Mar;36(3):1569-76. doi: 10.1016/j.neurobiolaging.2014.11.017. Epub 2014 Dec 12.
Glial cell line-derived neurotrophic factor (GDNF) helps protect dopaminergic neurons in the nigrostriatal tract. Although the cause of nigrostriatal degeneration is unknown, one theory is that excess glutamate from the subthalamic nucleus results in excitotoxic events in the substantia nigra (SN). Because dopaminergic degeneration is accompanied by a reduction in GDNF, we examined glutamate neurotransmission in the SN using a Gdnf heterozygous mouse model (Gdnf(+/-)) at 8 and 12 months of age. At 8 months, Gdnf(+/-) mice have greater glutamate release and higher basal glutamate levels, which precede the SN dopaminergic degeneration observed at 12 months of age. However, at 12 months, Gdnf(+/-) mice have lower basal levels of glutamate and less glutamate release than wild-type mice. Also at 8 months, Gdnf(+/-) mice have lower levels of glutamate transporter-1 and greater glial fibrillary acidic protein levels in the SN compared with wild-type mice, differences that increase with age. These data suggest that reduced levels of GDNF induce excess glutamate release and dysregulation of glutamate transporter-1, causing excitotoxicity in the SN that precedes dopaminergic degeneration.
胶质细胞系源性神经营养因子（GDNF）有助于保护黑质纹状体通路中的多巴胺能神经元。尽管黑质纹状体变性的病因尚不清楚，但有一种理论认为，来自丘脑底核的过量谷氨酸会导致黑质（SN）发生兴奋性毒性事件。由于多巴胺能变性伴随着GDNF的减少，我们使用Gdnf杂合小鼠模型（Gdnf(+/-)）在8个月和12个月大时检测了黑质中的谷氨酸神经传递。在8个月时，Gdnf(+/-)小鼠的谷氨酸释放量更高，基础谷氨酸水平也更高，这早于12个月大时观察到的黑质多巴胺能变性。然而，在12个月时，Gdnf(+/-)小鼠的基础谷氨酸水平低于野生型小鼠，谷氨酸释放量也更少。同样在8个月时，与野生型小鼠相比，Gdnf(+/-)小鼠黑质中的谷氨酸转运体-1水平更低，胶质纤维酸性蛋白水平更高，这些差异会随着年龄的增长而增加。这些数据表明，GDNF水平降低会导致谷氨酸释放过多和谷氨酸转运体-1失调，从而在多巴胺能变性之前在黑质中引起兴奋性毒性。
