Acute intermittent hypoxia-induced expression of brain-derived neurotrophic factor is disrupted in the brainstem of methyl-CpG-binding protein 2 null mice.

Rett syndrome is a neurodevelopmental disorder caused by loss of function mutations in the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2). One of its targets is the gene encoding brain-derived neurotrophic factor (bdnf). In vitro studies using cultured neurons have produced conflicting results with respect to the role of MeCP2 in BDNF expression. Acute intermittent hypoxia (AIH) induces plasticity in the respiratory system characterized by long-term facilitation of phrenic nerve amplitude. This paradigm induces an increase in BDNF protein. We hypothesized that AIH leads to augmentation of BDNF transcription in respiratory-related areas of the brainstem and that MeCP2 is necessary for this process. Wild-type and mecp2 null (mecp2−/y) mice were subjected to three 5-min episodes of exposure to 8% O2/4% CO2/88% N2, delivered at 5-min intervals. Normoxia control wild-type and mecp2 null mice were exposed to room air for the total length of time, i.e. 30 min. Following a recovery in room air, the pons and medulla were rapidly removed. Expression of BDNF protein and transcripts were determined by ELISA and quantitative PCR, respectively. AIH induced a significant increase in BDNF protein in the pons and medulla, and in mRNA transcript levels in the pons of wild-type animals. In contrast, there were no significant changes in either BDNF protein or transcripts in the pons or medulla of mice lacking Mecp2. The results indicate that Mecp2 is required for regulation of BDNF expression by acute intermittent hypoxia in vivo.

瑞特综合征是一种由编码转录因子甲基-CpG结合蛋白2（MeCP2）的基因发生功能缺失突变所导致的神经发育障碍。其作用靶点之一是编码脑源性神经营养因子（BDNF）的基因。利用培养的神经元进行的体外研究在MeCP2对BDNF表达的作用方面得出了相互矛盾的结果。急性间歇性缺氧（AIH）可诱导呼吸系统产生可塑性，其特征是膈神经振幅的长期易化。这种模式可诱导BDNF蛋白增加。我们假设AIH会导致脑干呼吸相关区域的BDNF转录增强，并且MeCP2对这一过程是必需的。野生型和mecp2基因缺失（mecp2−/y）小鼠接受3次每次5分钟的8% O₂/4% CO₂/88% N₂暴露，每次间隔5分钟。常氧对照的野生型和mecp2基因缺失小鼠在相同总时长（即30分钟）内暴露于室内空气。在室内空气中恢复后，迅速取出脑桥和延髓。分别通过酶联免疫吸附测定（ELISA）和定量聚合酶链反应（qPCR）测定BDNF蛋白和转录本的表达。AIH导致野生型动物脑桥和延髓中的BDNF蛋白以及脑桥中的mRNA转录水平显著增加。相比之下，缺乏Mecp2的小鼠脑桥或延髓中的BDNF蛋白或转录本均无显著变化。结果表明，在体内急性间歇性缺氧对BDNF表达的调节需要Mecp2。