Kholodilov Nikolai, Yarygina Olga, Oo Tinmarla Frances, Zhang Hui, Sulzer David, Dauer William, Burke Robert E
Department of Neurology, Psychiatry, Pharmacology, and Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
J Neurosci. 2004 Mar 24;24(12):3136-46. doi: 10.1523/JNEUROSCI.4506-03.2004.
Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine (DA) neurons in injury models and is being evaluated for the treatment of Parkinson's disease. Nevertheless, little is known of its physiological role. We have shown that GDNF suppresses apoptosis in DA neurons of the substantia nigra (SN) postnatally both in vitro and during their first phase of natural cell death in vivo. Furthermore, intrastriatal injection of neutralizing antibodies augments cell death, suggesting that endogenous GDNF plays a role as a target-derived factor. Such a role would predict that overexpression of GDNF in striatum would increase the surviving number of SN DA neurons. To test this hypothesis, we used the tetracycline-dependent transcription activator (tTA)/tTA-responsive promoter system to create mice that overexpress GDNF selectively in the striatum, cortex, and hippocampus. These mice demonstrate an increased number of SN DA neurons after the first phase of natural cell death. However, this increase does not persist into adulthood. As adults, these mice also do not have increased dopaminergic innervation of the striatum. They do, however, demonstrate increased numbers of ventral tegmental area (VTA) neurons and increased innervation of the cortex. This morphologic phenotype is associated with an increased locomotor response to amphetamine. We conclude that striatal GDNF is necessary and sufficient to regulate the number of SN DA neurons surviving the first phase of natural cell death, but it is not sufficient to increase their final adult number. GDNF in VTA targets, however, is sufficient to regulate the adult number of DA neurons.
胶质细胞源性神经营养因子（GDNF）已被证明在损伤模型中可保护并恢复多巴胺（DA）能神经元，目前正被评估用于治疗帕金森病。然而，对其生理作用却知之甚少。我们已经表明，GDNF在体外以及在体内自然细胞死亡的第一阶段均能抑制黑质（SN）中DA能神经元的凋亡。此外，纹状体内注射中和抗体可增加细胞死亡，这表明内源性GDNF作为一种靶源性因子发挥作用。这样的作用预示着纹状体内GDNF的过表达会增加SN中DA能神经元的存活数量。为了验证这一假设，我们使用四环素依赖性转录激活因子（tTA）/tTA反应性启动子系统来创建在纹状体、皮质和海马中选择性过表达GDNF的小鼠。这些小鼠在自然细胞死亡的第一阶段后显示SN中DA能神经元数量增加。然而，这种增加并未持续到成年期。成年后，这些小鼠纹状体的多巴胺能神经支配也没有增加。不过，它们确实显示腹侧被盖区（VTA）神经元数量增加以及皮质的神经支配增加。这种形态学表型与对苯丙胺的运动反应增加有关。我们得出结论，纹状体GDNF对于调节在自然细胞死亡第一阶段存活的SN中DA能神经元数量是必要且充分的，但不足以增加其最终的成年数量。然而，VTA靶点中的GDNF足以调节成年DA能神经元的数量。
