Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
Neurobiol Dis. 2012 Dec;48(3):271-81. doi: 10.1016/j.nbd.2012.07.012. Epub 2012 Jul 20.
Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons have been found in the striatum after dopamine depletion; however, little is known about the mechanism underlying their appearance or their functional significance. We previously showed an increase in striatal TH-ir neurons after L-DOPA treatment in mice with unilateral 6-OHDA lesions in the striatum. In the present study, we further examined the time-course and persistence of the effects of chronic L-DOPA treatment on the appearance and regulation of TH-ir neurons as well as their possible function. We found that the L-DOPA-induced increase in striatal TH-ir neurons is dose-dependent and persists for days after L-DOPA withdrawal, decreasing significantly 10 days after L-DOPA treatment ends. Using hemiparkinsonian D1 receptor knock-out (D1R-/-) and D2 receptor knock-out (D2R-/-) mice, we found that the D1R, but not the D2R, is required for the L-DOPA-induced appearance of TH-ir neurons in the dopamine-depleted striatum. Interestingly, our experiments in aphakia mice, which lack Pitx3 expression in the brain, indicate that the L-DOPA-dependent increase in the number of TH-ir neurons is independent of Pitx3, a transcription factor necessary for the development of mesencephalic dopaminergic neurons. To explore the possible function of L-DOPA-induced TH-ir neurons in the striatum, we examined dopamine overflow and forelimb use in L-DOPA-treated parkinsonian mice. These studies revealed a tight spatio-temporal correlation between the presence of striatal TH-ir neurons, the recovery of electrically stimulated dopamine overflow in the lesioned striatum, and the recovery of contralateral forelimb use with chronic L-DOPA treatment. Our results suggest that the presence of TH-ir neurons in the striatum may underlie the long-duration response to L-DOPA following withdrawal. Promotion of these neurons in the early stages of Parkinson's disease, when dopamine denervation is incomplete, may be beneficial for maintaining motor function.
酪氨酸羟化酶（TH）-免疫反应（ir）神经元在纹状体中被发现多巴胺耗竭后; 然而，对于它们出现的机制或其功能意义知之甚少。我们之前显示，在单侧 6-OHDA 损伤的纹状体中给予 L-DOPA 治疗后，纹状体中的 TH-ir 神经元增加。在本研究中，我们进一步检查了慢性 L-DOPA 治疗对 TH-ir 神经元出现和调节的时间过程和持久性，以及它们可能的功能。我们发现，L-DOPA 诱导的纹状体 TH-ir 神经元增加是剂量依赖性的，并在 L-DOPA 停药后持续数天，在 L-DOPA 治疗结束后 10 天显著减少。使用半帕金森病 D1 受体敲除（D1R-/-）和 D2 受体敲除（D2R-/-）小鼠，我们发现 D1R，但不是 D2R，是多巴胺耗竭纹状体中 L-DOPA 诱导的 TH-ir 神经元出现所必需的。有趣的是，我们在无晶状体小鼠中的实验表明，缺乏脑内 Pitx3 表达的无晶状体小鼠，表明 L-DOPA 依赖性 TH-ir 神经元数量的增加独立于 Pitx3，Pitx3 是中脑多巴胺能神经元发育所必需的转录因子。为了探索 L-DOPA 诱导的 TH-ir 神经元在纹状体中的可能功能，我们检查了帕金森病小鼠中 L-DOPA 治疗后的多巴胺溢出和前肢使用。这些研究表明，纹状体中存在 TH-ir 神经元，损伤纹状体中电刺激多巴胺溢出的恢复以及慢性 L-DOPA 治疗后对侧前肢使用的恢复之间存在紧密的时空相关性。我们的结果表明，TH-ir 神经元在纹状体中的存在可能是 L-DOPA 停药后长时间反应的基础。在多巴胺去神经不完全的帕金森病早期促进这些神经元可能有助于维持运动功能。
