Department of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany.
Elife. 2016 Oct 26;5:e19374. doi: 10.7554/eLife.19374.
Mutations in the gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons and . These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system.
基因中的突变导致神经发育障碍雷特综合征（RTT）。先前的研究表明，MeCP2 水平的改变导致神经突生长和谷氨酸能突触形成异常。然而，由于 MeCP2 已知可调节广泛的靶基因的转录，因此因果分子机制尚不清楚。在这里，我们描述了一个组成性 BDNF 前馈信号通路在调节谷氨酸能神经元的突触反应、总体生长和分化中的关键作用。慢性阻断 TrkB 受体可模拟野生型谷氨酸能神经元中 MeCP2 的缺乏，而 BDNF 的重新表达则定量挽救了 MeCP2 的缺乏。我们表明，BDNF 具有细胞自主性和自分泌作用，因为野生型神经元不能挽救相邻 MeCP2 缺乏神经元中的生长缺陷，而。这些发现对于理解 RTT 的病理生理学具有重要意义，其中野生型和突变型神经元在整个神经系统中相互混合。
