School of Biosciences, Cardiff University, Cardiff, United Kingdom; Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano.
Fondazione Santa Lucia, IRCCS, Rome.
Biol Psychiatry. 2015 Jan 15;77(2):106-15. doi: 10.1016/j.biopsych.2014.04.002. Epub 2014 Apr 12.
Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease.
Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured.
We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK.
These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA.
皮质纹状体突触的双向长期可塑性被认为是调节基底神经节系统中多巴胺介导的行为适应的核心细胞机制。直接和间接通路中的中间多棘神经元（MSN）的平衡活动对于正常纹状体功能至关重要。这种平衡在帕金森病和 l-3,4-二羟基苯丙氨酸（l-DOPA）诱导的运动障碍（LID）中被打破，这是当前帕金森病药物治疗的常见运动并发症。
在小鼠皮质纹状体切片制备中进行电生理记录。研究了突触可塑性，如长时程增强（LTP）和去极化。使用特定的药理学抑制剂或基因操作来调节 Ras-细胞外信号调节激酶（Ras-ERK）途径，这是一种涉及行为可塑性和不同纹状体神经元亚群突触活动的信号转导级联。
我们发现 Ras-ERK 途径不仅是高频刺激方案（HFS-LTP）诱导的背侧纹状体长期增强所必需的，也是其逆转，即突触去极化所必需的。 Ras-鸟嘌呤核苷酸释放因子 1（Ras-GRF1）的缺失，一种 Ras 蛋白的神经元激活剂，导致直接通路中的中间多棘神经元的 HFS-LTP 特异性丧失，而不影响间接通路中的 LTP。对单侧 6-羟多巴胺损伤（6-OHDA）动物的 LTP 分析显示，在慢性 L-DOPA 治疗下出现运动障碍的动物中，ERK 表现出复杂的、Ras-GRF1 和途径独立的、明显随机的参与。
这些数据不仅证明了 Ras-ERK 信号在纹状体 LTP、去极化和 L-DOPA 治疗后恢复中的核心作用，还揭示了多巴胺能神经支配和脉冲式 L-DOPA 给药后发生的多方面的突触适应。
