Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine
Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine
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DOI：
10.1523/jneurosci.21-14-05110.2001
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发表时间：
2001-07-15
影响因子：
5.3
通讯作者：
Bernardi, G
中科院分区：
文献类型：
--
作者：
Calabresi, P;Gubellini, P;Bernardi, G
异常不自主运动和认知障碍代表了亨廷顿病（HD）的典型临床症状。这种遗传性疾病涉及纹状体棘状神经元的变性，但不涉及纹状体大胆碱能中间神经元的变性，并且对应于HD患者脑中线粒体复合物II [琥珀酸脱氢酶（SD）]活性的显著降低。在这里，我们研究了SD抑制剂通过增加多巴胺能传递发挥毒性作用的可能性。我们报告，SD抑制剂，如3-硝基丙酸（3-NP），但不是线粒体复合物I的抑制剂，产生长时程增强的NMDA介导的突触兴奋（3-NP-LTP）在纹状体棘神经元。相反，这些抑制剂对纹状体胆碱能中间神经元和锥体皮质神经元的兴奋性突触传递没有影响。3-NP-LTP涉及细胞内钙离子增加和促分裂原活化蛋白激酶细胞外信号调节激酶的活化，并且严重依赖于通过D2受体起作用的内源性多巴胺，而它受D1受体负调控。因此，3-NP-LTP可能在HD中观察到的区域和细胞类型特异性神经元死亡中起关键作用。
Abnormal involuntary movements and cognitive impairment represent the classical clinical symptoms of Huntington's disease (HD). This genetic disorder involves degeneration of striatal spiny neurons, but not striatal large cholinergic interneurons, and corresponds to a marked decrease in the activity of mitochondrial complex II [succinate dehydrogenase (SD)] in the brains of HD patients. Here we have examined the possibility that SD inhibitors exert their toxic action by increasing glutamatergic transmission. We report that SD inhibitors such as 3-nitroproprionic acid (3-NP), but not an inhibitor of mitochondrial complex I, produce a long-term potentiation of the NMDA-mediated synaptic excitation (3-NP-LTP) in striatal spiny neurons. In contrast, these inhibitors had no effect on excitatory synaptic transmission in striatal cholinergic interneurons and pyramidal cortical neurons. 3-NP-LTP involves increased intracellular calcium and activation of the mitogen-activated protein kinase extracellular signal-regulated kinase and is critically dependent on endogenous dopamine acting via D2 receptors, whereas it is negatively regulated by D1 receptors. Thus 3-NP-LTP might play a key role in the regional and cell type-specific neuronal death observed in HD.