MeCP2 Dependent Transcriptional Repression & Neurotransmission

描述(申请人提供)：在过去的5年里，我们研究了MeCP2作为影响基因表达的转录因子在神经传递中的作用。我们的数据显示，MeCP2是突触功能的真正调节者，MeCP2的双向变化导致神经传递的互惠变化。我们还发现，在小鼠中，MeCP2表达的改变导致了几种行为表型，以及突触可塑性的特定测量的缺陷，进一步暗示MeCP2是突触过程的关键介质。在抑郁症领域的一个相当令人惊讶的发现是证明了东莨菪碱，一种M碱乙酰胆碱受体拮抗剂，在抑郁症患者中具有快速和持久的抗抑郁反应。我们已经开始研究东莨菪碱的抗抑郁作用机制，并发现它依赖于MeCP2的表达，因为这些作用在MeCP2基因敲除的小鼠中消失了。我们的研究结果还表明，东莨菪碱的抗抑郁作用依赖于MeCP2依赖的转录机制，导致BDNF表达增加，这对行为效应是重要的。我们的初步数据进一步表明，东莨菪碱可以触发丝氨酸421位MeCP2(PMeCP2)的磷酸化，这已被证明可以调节BDNF的表达。在最初的实验中，我们发现东莨菪碱通过阻断毒鼠强M1受体来触发pMeCP2。这项资助的目的是探索一种新的假设，即依赖于MeCP2的转录机制是东莨菪碱快速作用的抗抑郁作用的基础。我们将使用最先进的行为以及细胞和生化方法来检验我们的假设。总之，这些研究将有助于更好地了解快速作用抗抑郁药反应的潜在机制，并为将MeCP2调控作为治疗靶点提供新的见解。

DESCRIPTION (provided by applicant): 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.