MECP2 DEPENDENT TRANSCRIPTIONAL REPRESSION & NEUROTRANSMISSION

项目总结 在过去的5年里，我们研究了MeCP2在神经传递中作为一种 影响基因表达的转录因子。我们的数据显示，MeCP2是一种 突触功能的真实调节者与MeCP2的双向变化导致相互作用 神经传递的改变。我们还发现小鼠的MeCP2表达发生了变化 导致几种行为表型以及突触的特定测量缺陷 可塑性进一步表明MeCP2是突触过程的关键介质。一个相当不错的 在抑郁症领域的令人惊讶的发现是证明了东莨菪碱，一种 乙酰胆碱受体拮抗剂，具有快速、持久的抗抑郁作用 抑郁症患者的反应。我们已经开始研究这种疾病的机制。 东莨菪碱的抗抑郁作用，发现其依赖于MeCP2的表达 这些效应在MeCP2基因敲除小鼠中消失了。我们的发现还表明， 东莨菪碱的抗抑郁作用依赖于MeCP2依赖的转录 导致脑源性神经营养因子表达增加的机制对行为效应很重要。 我们的初步数据进一步表明，东莨菪碱在 丝氨酸421(PMeCP2)，已被证明调节BDNF的表达。在首字母中 实验中，我们发现东莨菪碱通过阻断毒鼠强M1受体发挥作用。 触发pMeCP2。这笔赠款的目的是探索新的假设，MeCP2- 依赖的转录机制是其快速抗抑郁作用的基础 东莨菪碱。我们将使用最先进的行为以及细胞和生化 检验我们假设的方法。总的来说，这些研究将有助于更好地 了解快速抗抑郁药反应的潜在机制以及 为作为治疗靶点的MeCP2调节提供新的见解。

PROJECT SUMMARY Over the past ~5 years, we have examined the role of MeCP2 in neurotransmission as a transcriptional factor impacting gene expression. Our data has revealed that MeCP2 is a bona fide regulator of synaptic function with bidirectional changes in MeCP2 resulting in reciprocal alterations in neurotransmission. We have also shown alterations in MeCP2 expression in mice result in several behavioral phenotypes as well as deficits in specific measures of synaptic plasticity further implicating MeCP2 as a key mediator of synaptic processes. A rather surprising finding in the field of depression has been the demonstration that scopolamine, a muscarinic acetylcholine receptor antagonist, has rapid and long-lasting antidepressant responses in depressed individuals. We have started to investigate the mechanism of the antidepressant action of scopolamine, and have found it is dependent on MeCP2 expression as these effects are lost in Mecp2 knockout mice. Our findings also suggest that the antidepressant effects of scopolamine are dependent on MeCP2-dependent transcriptional mechanisms resulting in increased BDNF expression that is important for the behavioral effects. Our preliminary data further suggests that scopolamine triggers MeCP2 phosphorylation at Serine 421 (pMeCP2), which has been shown to regulate BDNF expression. In initial experiments, we find that scopolamine acts via blockade of the muscarinic M1 receptor to trigger pMeCP2. The objective of this grant is to explore the novel hypothesis that MeCP2- dependent transcriptional mechanisms underlie the fast acting antidepressant effects of scopolamine. We will use state of the art behavioral as well as cellular and biochemical approaches to examine our hypothesis. Collectively, these studies will contribute to a better understanding of mechanisms underlying fast-acting antidepressant responses as well as provide novel insight into MeCP2 regulation as a therapeutic target.