Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
Eur J Neurosci. 2010 Feb;31(3):478-90. doi: 10.1111/j.1460-9568.2010.07077.x. Epub 2010 Jan 25.
Dopamine deficiency associated with Parkinson's disease (PD) results in numerous changes in striatal transmitter function and neuron morphology. Specifically, there is marked atrophy of dendrites and dendritic spines on striatal medium spiny neurons (MSN), primary targets of inputs from nigral dopamine and cortical glutamate neurons, in advanced PD and rodent models of severe dopamine depletion. Dendritic spine loss occurs via dysregulation of intraspine Cav1.3 L-type Ca(2+)channels and can be prevented, in animal models, by administration of the calcium channel antagonist, nimodipine. The impact of MSN dendritic spine loss in the parkinsonian striatum on dopamine neuron graft therapy remains unexamined. Using unilaterally parkinsonian Sprague-Dawley rats, we tested the hypothesis that MSN dendritic spine preservation through administration of nimodipine would result in improved therapeutic benefit and diminished graft-induced behavioral abnormalities in rats grafted with embryonic ventral midbrain cells. Analysis of rotational asymmetry and spontaneous forelimb use in the cylinder task found no significant effect of dendritic spine preservation in grafted rats. However, analyses of vibrissae-induced forelimb use, levodopa-induced dyskinesias and graft-induced dyskinesias showed significant improvement in rats with dopamine grafts associated with preserved striatal dendritic spine density. Nimodipine treatment in this model did not impact dopamine graft survival but allowed for increased graft reinnervation of striatum. Taken together, these results demonstrate that even with grafting suboptimal numbers of cells, maintaining normal spine density on target MSNs results in overall superior behavioral efficacy of dopamine grafts.
帕金森病（PD）与多巴胺缺乏相关，导致纹状体递质功能和神经元形态发生许多变化。具体而言，在晚期 PD 和严重多巴胺耗竭的啮齿动物模型中，纹状体中间神经元（MSN）的树突和树突棘明显萎缩，这些 MSN 是黑质多巴胺和皮质谷氨酸神经元输入的主要靶标。树突棘丢失是通过树突棘内 Cav1.3 L 型钙通道的失调发生的，可以通过给予钙通道拮抗剂尼莫地平在动物模型中预防。MSN 树突棘丢失对帕金森纹状体中多巴胺神经元移植治疗的影响尚未得到检验。使用单侧帕金森病 Sprague-Dawley 大鼠，我们检验了通过给予尼莫地平保留 MSN 树突棘会导致胚胎中脑腹侧细胞移植的大鼠中治疗效益提高和移植诱导的行为异常减少的假设。在旋转不对称和圆柱体任务中的自发前肢使用分析中，未发现移植大鼠中树突棘保留有显著影响。然而，在触须诱导的前肢使用、左旋多巴诱导的运动障碍和移植诱导的运动障碍的分析中，与纹状体树突棘密度保持正常的多巴胺移植相关的大鼠表现出显著改善。在该模型中，尼莫地平治疗不会影响多巴胺移植的存活，但允许增加移植对纹状体的再神经支配。总之，这些结果表明，即使移植的细胞数量不理想，维持目标 MSN 上正常的棘密度也会导致多巴胺移植的整体行为疗效更优。
