Laboratorio di Neurofisiologia, Fondazione Santa Lucia IRCCS, 00143 Rome, Italy.
Adv Exp Med Biol. 2012;970:553-72. doi: 10.1007/978-3-7091-0932-8_24.
Activity-dependent modifications in synaptic efficacy, such as long-term depression (LTD) and long-term potentiation (LTP), represent key cellular substrates for adaptive motor control and procedural memory. The impairment of these two forms of synaptic plasticity in the nucleus striatum could account for the onset and the progression of motor and cognitive symptoms of Parkinson's disease (PD), characterized by the massive degeneration of dopaminergic neurons. In fact, both LTD and LTP are peculiarly controlled and modulated by dopaminergic transmission coming from nigrostriatal terminals. Changes in corticostriatal and nigrostriatal neuronal excitability may influence profoundly the threshold for the induction of synaptic plasticity, and changes in striatal synaptic transmission efficacy are supposed to play a role in the occurrence of PD symptoms. Understanding of these maladaptive forms of synaptic plasticity has mostly come from the analysis of experimental animal models of PD. A series of cellular and synaptic alterations occur in the striatum of experimental parkinsonism in response to the massive dopaminergic loss. In particular, dysfunctions in trafficking and subunit composition of glutamatergic NMDA receptors on striatal efferent neurons contribute to the clinical features of the experimental parkinsonism. Interestingly, it has become increasingly evident that in striatal spiny neurons, the correct assembly of NMDA receptor complex at the postsynaptic site is a major player in early phases of PD, and it is sensitive to distinct degrees of DA denervation. The molecular defects at the basis of PD progression may be not confined just at the postsynaptic neuron: accumulating evidences have recently shown that the genes linked to PD play a critical role at the presynaptic site. DA release into the synaptic cleft relies on a proper presynaptic vesicular transport; impairment of SV trafficking, modification of DA flow, and altered presynaptic plasticity have been described in several PD animal models. Furthermore, an impaired DA turnover has been described in presymptomatic PD patients. Thus, given the pathological events occurring precociously at the synapses of PD patients, post- and presynaptic sites may represent an adequate target for early therapeutic intervention.
突触效能的活动依赖性改变，如长时程抑郁（LTD）和长时程增强（LTP），是适应运动控制和程序性记忆的关键细胞基础。纹状体中这两种形式的突触可塑性的损伤可能导致帕金森病（PD）的运动和认知症状的发作和进展，其特征是多巴胺能神经元的大量退化。事实上，LTD 和 LTP 都受到来自黑质纹状体末端的多巴胺传递的特殊控制和调节。皮质纹状体和黑质纹状体神经元兴奋性的变化可能会深刻地影响诱导突触可塑性的阈值，而纹状体突触传递效能的变化可能在 PD 症状的发生中发挥作用。对这些适应性突触可塑性形式的理解主要来自于 PD 实验动物模型的分析。在实验性帕金森病中，纹状体发生了一系列的细胞和突触改变，以应对多巴胺的大量丧失。特别是，纹状体传出神经元上谷氨酸能 NMDA 受体的运输和亚基组成功能障碍导致了实验性帕金森病的临床特征。有趣的是，越来越明显的是，在纹状体棘状神经元中，NMDA 受体复合物在突触后位点的正确组装是 PD 早期的主要参与者，并且对不同程度的 DA 去神经支配敏感。PD 进展的分子缺陷可能不仅局限于突触后神经元：最近的大量证据表明，与 PD 相关的基因在突触前位点发挥着关键作用。DA 释放到突触小泡依赖于适当的突触前囊泡运输；在几种 PD 动物模型中已经描述了 SV 运输受损、DA 流改变和突触前可塑性改变。此外，在 PD 患者的亚临床阶段已经描述了 DA 周转率受损。因此，鉴于 PD 患者突触发生的病理事件早发，突触后和突触前部位可能是早期治疗干预的适当靶点。
