Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson’s disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson’s disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson’s disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson’s disease, and that might be relevant for other striatal pathologies, such as drug abuse.

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纹状体神经元的运动学习和可塑性：与帕金森氏病的相关性

纹状体多巴胺的黑质传递是广泛的神经元功能（包括技能学习）的核心，而这种功能在帕金森氏病等几种病理中均受到干扰。突触可塑性机制，通过其最初的运动学习被长期存储在纹状体神经元中，然后在随后的训练中逐渐优化，至今仍未得到探索。解决这一问题对于确定参与帕金森氏病纹状体依赖性学习障碍的突触和分子机制至关重要。在这项研究中，我们利用远交啮齿动物之间的个体差异在轮转增量运动学习协议中达到高原表现，以离体研究纹状体突触可塑性。然后，我们评估了该过程如何受到多巴胺受体和多巴胺活性转运蛋白的调节，以及是否由于中脑中人α-突触核蛋白的过表达而受到损害；后者是帕金森氏病的进行性动物模型。我们发现，根据纹状体中棘神经元的长期抑制方案，运动学习的初始习性诱导了多巴胺活性转运蛋白和D1受体介导的长期增强作用。这种作用在达到性能稳定期的动物中消失了。人类α-突触核蛋白的过表达降低了纹状体多巴胺的活性转运蛋白水平，损害了运动学习，并阻止了由学习引起的长期增强作用，直到出现多巴胺神经元丧失。我们的发现提供了在技能获得过程中由多巴胺受体和多巴胺活性转运蛋白介导的背外侧纹状体中细胞可塑性重组的证据。这种新近确定的细胞记忆机制是一种可塑性的形成，在突触核蛋白病（如帕金森氏病）的早期被破坏，并且可能与其他纹状体疾病（如药物滥用）有关。