Three Mechanisms by which Striatal Denervation Causes Breakdown of Dopamine Signaling
Three Mechanisms by which Striatal Denervation Causes Breakdown of Dopamine Signaling
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DOI：
10.1523/jneurosci.1458-14.2014
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发表时间：
2014-09-10
影响因子：
5.3
通讯作者：
Dreyer, Jakob K.
中科院分区：
文献类型：
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作者：
Dreyer, Jakob K.
黑质纹状体多巴胺（DA）神经元的进行性丢失是帕金森病（PD）的神经病理学标志。这种疾病的症状通常可以通过DAD（2）激动剂治疗，因此似乎与间接纹状体通路的去抑制有关。然而，没有证据表明症状是由细胞外DA浓度低引起的，或者与D-2受体结合减少有关。在这里，我提供了一个理论分析的病理生理学和突触后适应纹状体DA去神经。我发现，进行性去神经支配可能会改变DA信号通过三个独立的机制取决于程度的去神经和宏观形态的病变。只要剩余的神经支配保持解剖学连贯性，去神经支配减少细胞外DA的相位变化，但DA张力不变。阶段性信号传导的减少可以通过上调突触后信号传导级联来部分补偿。然而，DA动态的变化逃避补偿。在80-99%去神经支配的情况下，由强直性DA释放的随机波动引起的D-2调节通路中产生持续的异常信号。永久性低DA水平发生在完全缺乏神经支配的区域。模拟左旋多巴治疗减少了异常的D-2信号。在高度失神经支配的情况下，左旋多巴增强了另一个异常信号，这次是在D-1通路中。该分析提供了对PD早期和晚期、主要治疗药物的作用和潜在副作用的定量、生理学一致的观点。这里描述的机制也可以提供一个解释目前无法解释的病理现象，如精神兴奋剂诱导的动物模型中的逆向旋转。
Progressive loss of nigrostriatal dopamine (DA) neurons is the neuropathological hallmark of Parkinson's disease (PD). Symptoms of the disease can often be treated by DAD(2) agonists and thus seem related to disinhibition of the indirect striatal pathway. However, there is no evidence that symptoms arise by low extracellular DA concentration or are associated with reduced D-2 receptor binding. Here I provide a theoretical analysis of the pathophysiology and postsynaptic adaptation resulting from striatal DA denervation. I found that progressive denervation may alter DA signaling by three independent mechanisms depending on degree of denervation and macroscopic morphology of the lesion. As long as the remaining innervation stays anatomically coherent, denervation reduces phasic variations in extracellular DA, but the DA tone is not changed. The reduction of phasic signaling can be partially compensated by upregulating postsynaptic signaling cascades. However, changes in DA dynamics evade compensation. With 80-99% denervation, a persistent aberrant signal develops in D-2-regulated pathways caused by random fluctuations in tonic DA release. Permanent low DA levels occur in regions completely void of innervation. Simulation of L-dopa therapy reduced the aberrant D-2 signal. With a high degree of denervation, L-dopa enhanced another aberrant signal, this time in the D-1 pathway. This analysis provides a quantitative, physiologically consistent view of the early and late stages of PD, the effect of main therapeutic medications, and potential side effects. The mechanisms described here may also provide an explanation to currently inexplicable pathological phenomena such as psycho stimulant-induced contraversive rotations in animal models.