Synaptic Dysfunction in Parkinson's Disease
Synaptic Dysfunction in Parkinson's Disease
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DOI：
10.1007/978-3-7091-0932-8_24
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发表时间：
2012-01-01
期刊：
影响因子：
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通讯作者：
Calabresi, Paolo
中科院分区：
文献类型：
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作者：
Picconi, Barbara;Piccoli, Giovanni;Calabresi, Paolo
突触效能的活动依赖性修饰，如长时程抑制（LTD）和长时程增强（LTP），代表了适应性运动控制和程序性记忆的关键细胞底物。这两种形式的突触可塑性在纹状体核的损害可以解释帕金森病（PD）的运动和认知症状的发作和进展，其特征在于多巴胺能神经元的大量变性。事实上，LTD和LTP都受到来自黑质纹状体末梢的多巴胺能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深刻地影响突触可塑性诱导的阈值，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。对这些适应不良形式的突触可塑性的理解主要来自对PD实验动物模型的分析。实验性帕金森病患者纹状体内大量多巴胺能神经元丢失后发生一系列细胞和突触改变。特别是，纹状体传出神经元上的NMDA受体的运输和亚单位组成的功能障碍有助于实验性帕金森病的临床特征。有趣的是，它已变得越来越明显，在纹状体棘状神经元，在突触后位点的NMDA受体复合物的正确组装是PD早期阶段的主要参与者，并且它对不同程度的DA去神经支配敏感。PD进展基础上的分子缺陷可能不仅仅局限于突触后神经元：最近越来越多的证据表明，与PD相关的基因在突触前位点起着关键作用。DA释放到突触间隙依赖于一个适当的突触前囊泡运输，SV贩运，修改DA流量，并改变突触前可塑性的损害已被描述在几个PD动物模型。此外，已在症状前PD患者中描述了受损的DA周转。因此，考虑到PD患者突触处过早发生的病理事件，突触后和突触前位点可能是早期治疗干预的适当靶点。
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.