Bernstein Center for Computational Neuroscience, Charité - Universitätsmedizin Berlin, Berlin, Germany; Psychology, Humboldt Universität zu Berlin, Berlin, Germany; Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Computer Science, Chemnitz University of Technology, Straße der Nationen 62, Chemnitz, Germany.
Eur J Neurosci. 2014 Feb;39(4):688-702. doi: 10.1111/ejn.12434. Epub 2013 Dec 9.
In Parkinson's disease, a loss of dopamine neurons causes severe motor impairments. These motor impairments have long been thought to result exclusively from immediate effects of dopamine loss on neuronal firing in basal ganglia, causing imbalances of basal ganglia pathways. However, motor impairments and pathway imbalances may also result from dysfunctional synaptic plasticity - a novel concept of how Parkinsonian symptoms evolve. Here we built a neuro-computational model that allows us to simulate the effects of dopamine loss on synaptic plasticity in basal ganglia. Our simulations confirm that dysfunctional synaptic plasticity can indeed explain the emergence of both motor impairments and pathway imbalances in Parkinson's disease, thus corroborating the novel concept. By predicting that dysfunctional plasticity results not only in reduced activation of desired responses, but also in their active inhibition, our simulations provide novel testable predictions. When simulating dopamine replacement therapy (which is a standard treatment in clinical practice), we observe a new balance of pathway outputs, rather than a simple restoration of non-Parkinsonian states. In addition, high doses of replacement are shown to result in overshooting motor activity, in line with empirical evidence. Finally, our simulations provide an explanation for the intensely debated paradox that focused basal ganglia lesions alleviate Parkinsonian symptoms, but do not impair performance in healthy animals. Overall, our simulations suggest that the effects of dopamine loss on synaptic plasticity play an essential role in the development of Parkinsonian symptoms, thus arguing for a re-conceptualisation of Parkinsonian pathophysiology.
在帕金森病中，多巴胺神经元的丧失导致严重的运动障碍。长期以来，人们一直认为这些运动障碍仅源自多巴胺丧失对基底神经节神经元放电的直接影响，导致基底神经节通路失衡。然而，运动障碍和通路失衡也可能源于功能失调的突触可塑性——这是帕金森症状演变的一个新概念。在这里，我们构建了一个神经计算模型，该模型允许我们模拟多巴胺丧失对基底神经节突触可塑性的影响。我们的模拟证实，功能失调的突触可塑性确实可以解释帕金森病中运动障碍和通路失衡的出现，从而证实了这一新概念。通过预测功能失调的可塑性不仅导致期望反应的激活减少，而且还导致其主动抑制，我们的模拟提供了新的可测试预测。当模拟多巴胺替代疗法（这是临床实践中的标准治疗方法）时，我们观察到通路输出的新平衡，而不是简单地恢复非帕金森状态。此外，高剂量的替代疗法会导致运动活动过度，这与经验证据一致。最后，我们的模拟为一个激烈争论的悖论提供了解释，即集中的基底神经节损伤可以缓解帕金森症状，但不会损害健康动物的表现。总的来说，我们的模拟表明，多巴胺丧失对突触可塑性的影响在帕金森症状的发展中起着至关重要的作用，因此主张重新概念化帕金森病的病理生理学。
