A critical and cell-autonomous role for MeCP2 in synaptic scaling up.
A critical and cell-autonomous role for MeCP2 in synaptic scaling up.
复制标题
DOI：
10.1523/jneurosci.3077-12.2012
复制
发表时间：
2012-09-26
期刊：
影响因子：
--
通讯作者：
Turrigiano GG
中科院分区：
文献类型：
--
作者：
Blackman MP;Djukic B;Nelson SB;Turrigiano GG
Rett综合征是女性智力低下的主要遗传原因。Rett的大多数病例是由于编码转录调节因子甲基-CpG结合蛋白2（MeCP 2）的基因中的功能突变的丧失，但是尽管进行了大量的努力，仍然不清楚MeCP 2功能的丧失如何产生Rett的神经缺陷。在这里，我们表明，MeCP 2起着重要的和细胞自主的作用，在稳态突触放大响应减少放电或减少感觉驱动在大鼠视觉皮层锥体神经元。我们发现，MeCP 2的急性RNAi敲低阻断了靶向新皮质锥体神经元内的突触缩放。此外，MeCP 2敲低降低兴奋性突触数量，而不影响基础mEPSC振幅或备用突触处的AMPAR积累，表明MeCP 2细胞自主地起作用以维持个体新皮层神经元中的兴奋性突触数量和突触缩放。最后，我们使用Rett的小鼠模型来表明MeCP 2损失阻止体内响应于视觉剥夺的稳态突触扩大，首次证明MeCP 2损失破坏了完整发育中的新皮层内的稳态可塑性。我们的研究结果建立了MeCP 2作为突触缩放的关键介质，并提出了Rett的一些神经缺陷来自稳态可塑性破坏的可能性。
Rett syndrome is the leading genetic cause of mental retardation in females. Most cases of Rett are due to loss of function mutations in the gene coding for the transcriptional regulator methyl-CpG binding protein 2 (MeCP2), but despite much effort it remains unclear how a loss of MeCP2 function generates the neurological deficits of Rett. Here we show that MeCP2 plays an essential and cell-autonomous role in homeostatic synaptic scaling up in response to reduced firing or reduced sensory drive in rat visual cortical pyramidal neurons. We found that acute RNAi knockdown of MeCP2 blocked synaptic scaling within targeted neocortical pyramidal neurons. Further, MeCP2 knockdown decreased excitatory synapse number without affecting basal mEPSC amplitude or AMPAR accumulation at spared synapses, demonstrating that MeCP2 acts cell-autonomously to maintain both excitatory synapse number and synaptic scaling in individual neocortical neurons. Finally, we used a mouse model of Rett to show that MeCP2 loss prevents homeostatic synaptic scaling up in response to visual deprivation in vivo, demonstrating for the first time that MeCP2 loss disrupts homeostatic plasticity within the intact developing neocortex. Our results establish MeCP2 as a critical mediator of synaptic scaling, and raise the possibility that some of the neurological defects of Rett arise from a disruption of homeostatic plasticity.