Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Neurosci. 2011 Aug 31;31(35):12629-37. doi: 10.1523/JNEUROSCI.0684-11.2011.
Mutations in the methyl-CpG-binding protein 2 (MeCP2) result in Rett syndrome (RTT), an X-linked disorder that disrupts neurodevelopment. Girls with RTT exhibit motor deficits similar to those in Parkinson's disease, suggesting defects in the nigrostriatal pathway. This study examined age-dependent changes in dopamine neurons of the substantia nigra (SN) from wild-type, presymptomatic, and symptomatic Mecp2(+/-) mice. Mecp2(+) neurons in the SN in Mecp2(+/-) mice were indistinguishable in morphology, resting conductance, and dopamine current density from neurons in wild-type mice. However, the capacitance, total dendritic length, and resting conductance of Mecp2(-) neurons were less than those of Mecp2(+) neurons as early as 4 weeks after birth, before overt symptoms. These differences were maintained throughout life. In symptomatic Mecp2(+/-) mice, the current induced by activation of D(2) dopamine autoreceptors was significantly less in Mecp2(-) neurons than in Mecp2(+) neurons, although D(2) receptor density was unaltered in Mecp2(+/-) mice. Electrochemical measurements revealed that significantly less dopamine was released after stimulation of striatum in adult Mecp2(+/-) mice compared to wild type. The decrease in size and function of Mecp2(-) neurons observed in adult Mecp2(+/-) mice was recapitulated in dopamine neurons from symptomatic Mecp2(-/y) males. These results show that mutation in Mecp2 results in cell-autonomous defects in the SN early in life and throughout adulthood. Ultimately, dysfunction in terminal dopamine release and D(2) autoreceptor-dependent currents in dopamine neurons from symptomatic females support the idea that decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT in Mecp2(+/-) mice.
甲基化CpG 结合蛋白 2（MeCP2）突变导致雷特综合征（RTT），这是一种破坏神经发育的 X 连锁疾病。患有 RTT 的女孩表现出与帕金森病相似的运动缺陷，表明黑质纹状体通路存在缺陷。本研究检查了来自野生型、无症状和有症状 Mecp2(+/-) 小鼠的黑质（SN）多巴胺神经元的年龄依赖性变化。SN 中的 Mecp2(+) 神经元在形态、静息电导和多巴胺电流密度方面与野生型小鼠的神经元无法区分。然而，早在出生后 4 周，即出现明显症状之前，Mecp2(-) 神经元的电容、总树突长度和静息电导就小于 Mecp2(+) 神经元。这些差异在整个生命周期中都得以维持。在有症状的 Mecp2(+/-) 小鼠中，D2 多巴胺自受体激活诱导的电流在 Mecp2(-) 神经元中明显小于 Mecp2(+) 神经元，尽管 D2 受体密度在 Mecp2(+/-) 小鼠中没有改变。电化学测量显示，与野生型相比，成年 Mecp2(+/-) 小鼠纹状体刺激后多巴胺的释放明显减少。成年 Mecp2(+/-) 小鼠中观察到的 Mecp2(-) 神经元的大小和功能下降在 Mecp2(-/y) 雄性的多巴胺神经元中得到了重现。这些结果表明，Mecp2 突变导致生命早期和成年后 SN 中的神经元自主缺陷。最终，来自有症状雌性的多巴胺神经元中末端多巴胺释放和 D2 自受体依赖性电流的功能障碍支持这样的观点，即由于 Mecp2 表达的异质性导致多巴胺传递减少，导致 Mecp2(+/-) 小鼠 RTT 的帕金森特征。
