Higher free d-aspartate and N-methyl-d-aspartate levels prevent striatal depotentiation and anticipate 1-DOPA-induced dyskinesia
Higher free d-aspartate and N-methyl-d-aspartate levels prevent striatal depotentiation and anticipate 1-DOPA-induced dyskinesia
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DOI：
10.1016/j.expneurol.2011.09.013
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发表时间：
2011-12-01
影响因子：
5.3
通讯作者：
Usiello, Alessandro
中科院分区：
文献类型：
--
作者：
Errico, Francesco;Bonito-Oliva, Alessandra;Usiello, Alessandro
在帕金森病(PD)中，纹状体N-甲基-D-天冬氨酸受体(NMDAR)信号的进行性改变已成为长期服用左旋多巴(L-多巴)引起不良运动效应的一个重要因素。在这方面，NMDAR通道阻滞剂金刚烷胺是迄今为止临床上唯一可用于减轻L-多巴诱导的运动障碍(LID)的药物。在这项研究中，我们使用缺乏D-天冬氨酸氧化酶(DDO)酶的遗传性小鼠模型(DDO(-/-)小鼠)，研究了基础皮质纹状体高谷氨酸能传递对运动障碍的影响。我们发现，在DDO(-/-)小鼠中，高水平的内源性游离D-天冬氨酸(D-Asp)和NMDA(已知刺激NMDAR传递)导致皮质纹状体突触去增强和LID早熟表达。有趣的是，与6-羟基多巴胺损伤和L-多巴治疗相关的多巴胺能传递的任何变化都先于去增强的阻断。事实上，受损的突变小鼠表现出生理上的L-多巴依赖的纹状体D1受体/蛋白激酶A/蛋白磷酸酶-1和ERK信号的增强。此外，与运动障碍动物模型中发生的NMDAR亚单位的突触重排一致，短暂的L-多巴治疗使DDO(-/-)损毁突变的纹状体突触后部分的NR2B亚单位显著和选择性地减少，但在对照组中没有。这些数据表明，DDO(-/-)小鼠NMDAR上预先存在的高谷氨酸能张力会产生异常的纹状体突触变化，进而促进LID的发生。(C)2011 Elsevier Inc.保留所有权利。
In Parkinson's disease (PD) progressive alteration of striatal N-methyl-D-aspartate receptors (NMDARs) signaling has emerged as a considerable factor for the onset of the adverse motor effects of long-term levodopa (L-DOPA) treatment. In this regard, the NMDAR channel blocker amantadine is so far the only drug available for clinical use that attenuates L-DOPA-induced dyskinesia (LID). In this study, we examined the influence of a basal corticostriatal hyper-glutamatergic transmission in the appearance of dyskinesia, using a genetic mouse model lacking D-Aspartate Oxidase (DDO) enzyme (Ddo(-/-)mice). We found that, in Ddo(-/-)mice, non-physiological, high levels of the endogenous free D-amino acids D-aspartate (D-Asp) and NMDA, known to stimulate NMDAR transmission, resulted in the loss of corticostriatal synaptic depotentiation and precocious expression of LID. Interestingly, the block of depotentiation precedes any change in dopaminergic transmission associated to 6-OHDA lesion and L-DOPA treatment. Indeed, lesioned mutant mice display physiological L-DOPA-dependent enhancement of striatal D1 receptor/PKA/protein phosphatase-1 and ERK signaling. Moreover, in line with synaptic rearrangements of NMDAR subunits occurring in dyskinetic animal models, a short L-DOPA treatment produces a dramatic and selective reduction of the NR2B subunit in the striatal post-synaptic fraction of Ddo(-/-) lesioned mutants but not in controls. These data indicate that a preexisting hyper-glutamatergic tone at NMDARs in Ddo(-/-) mice produce abnormal striatal synaptic changes that, in turn, facilitate the onset of LID. (C) 2011 Elsevier Inc. All rights reserved.