Li Li, Sagot Ben, Zhou Fu-Ming
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA; School of Biotechnology, Southern Medical University, Guangzhou, China.
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Brain Res. 2015 Jul 30;1615:12-21. doi: 10.1016/j.brainres.2015.04.011. Epub 2015 May 7.
The transcription factor Pitx3 null mutant (Pitx3Null) mice have a constitutive perinatal-onset and symmetric bilateral dopamine (DA) loss in the striatum. In these mice l-3,4-dihydroxyphenylalanine (l-dopa) induces apparently normal horizontal movements (walking) but also upward movements consisting of the vertical body trunk and waving paws that are absent in normal animals and in animals with the classic unilateral 6-hydroxydopamine (6-OHDA) lesion-induced DA denervation. Thus, a concern is that the perinatal timing of the DA loss and potential developmental abnormalities in Pitx3Null mice may underlie these upward movements, thus reducing the usefulness as a DA denervation model. Here we show that in normal wild-type (Pitx3WT) mice with adult-onset symmetric, bilateral 6-OHDA-induced DA lesion in the dorsal striatum, l-dopa induces normal horizontal movements and upward movements that are qualitatively identical to those in Pitx3Null mice. Furthermore, after unilateral 6-OHDA lesion of the residual DA innervation in the striatum in Pitx3Null mice, l-dopa induces contraversive rotation that is similar to that in Pitx3WT mice with the classic unilateral 6-OHDA lesion. These results indicate that in Pitx3Null mice, the bilateral symmetric DA denervation in the dorsal striatum is sufficient for expressing the l-dopa-induced motor phenotype and the perinatal timing of their DA loss is not a determining factor, providing further evidence that Pitx3Null mice are a convenient and suitable mouse model to study the consequences of DA loss and dopaminergic replacement therapy in Parkinson's disease.
转录因子Pitx3基因敲除突变体（Pitx3Null）小鼠在纹状体中存在围产期起始且对称的双侧多巴胺（DA）缺失。在这些小鼠中，左旋多巴（l-dopa）可诱导明显正常的水平运动（行走），但也会引发由垂直身体躯干和挥动爪子组成的向上运动，而正常动物以及患有经典单侧6-羟基多巴胺（6-OHDA）损伤诱导的DA去神经支配的动物则不会出现这种情况。因此，人们担心Pitx3Null小鼠中DA缺失的围产期时机以及潜在的发育异常可能是这些向上运动的基础，从而降低了其作为DA去神经支配模型的实用性。在此我们表明，在成年期起始出现对称双侧6-OHDA诱导的背侧纹状体DA损伤的正常野生型（Pitx3WT）小鼠中，l-dopa诱导的正常水平运动和向上运动在性质上与Pitx3Null小鼠中的相同。此外，在Pitx3Null小鼠纹状体中残留DA神经支配进行单侧6-OHDA损伤后，l-dopa诱导的对侧旋转与具有经典单侧6-OHDA损伤的Pitx3WT小鼠相似。这些结果表明，在Pitx3Null小鼠中，背侧纹状体中的双侧对称DA去神经支配足以表达l-dopa诱导的运动表型，并且其DA缺失的围产期时机不是决定因素，这进一步证明Pitx3Null小鼠是研究帕金森病中DA缺失后果和多巴胺能替代疗法的便捷且合适的小鼠模型。
