Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons
Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons
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DOI：
10.1073/pnas.1831768100
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发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
Caron, MG
中科院分区：
文献类型：
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作者：
Cyr, M;Beaulieu, JM;Caron, MG
多巴胺被认为有助于脑中含多巴胺神经元的变性。然而，多巴胺是否影响其他神经元群体的存活仍不清楚。在这里，我们的文件，持续升高的细胞外多巴胺，多巴胺转运蛋白基因失活的结果，偶尔发展严重的运动障碍症状伴随着纹状体多巴胺反应性γ-氨基丁酸能神经元的凋亡死亡。多巴胺合成的长期抑制可以防止运动功能障碍的出现。神经元死亡与多巴胺能信号传导的过度激活相关，如纹状体DeltaFosB、细胞周期蛋白依赖性激酶5和p35的强烈上调所证明的。此外，在有症状的小鼠中观察到tau蛋白的过度磷酸化，这是一种与几种神经退行性疾病中的细胞周期蛋白依赖性激酶5的活化相关的现象。这些发现提供了体内证据，除了其在多巴胺神经元变性中的作用外，多巴胺还可以通过以前未被认识到的机制导致其靶神经元的选择性死亡。
Dopamine is believed to contribute to the degeneration of dopamine-containing neurons in the brain. However, whether dopamine affects the survival of other neuronal populations has remained unclear. Here we document that mice with persistently elevated extracellular dopamine, resulting from inactivation of the dopamine transporter gene, sporadically develop severe symptoms of dyskinesia concomitant with apoptotic death of striatal dopamine-responsive gamma-aminobutyric acidergic neurons. Chronic inhibition of dopamine synthesis prevents the appearance of motor dysfunction. The neuronal death is associated with overactivation of dopaminergic signaling as evidenced by the robust up-regulation of striatal DeltaFosB, cyclin-dependent kinase 5, and p35. Moreover, hyperphosphorylation of the tau protein, a phenomenon associated with the activation of cyclin-dependent kinase 5 in several neurodegenerative disorders, is observed in symptomatic mice. These findings provide in vivo evidence that, in addition to its proposed role in the degeneration of dopamine neurons, dopamine can also contribute to the selective death of its target neurons via a previously unappreciated mechanism.