MECP2 DEPENDENT TRANSCRIPTIONAL REPRESSION & NEUROTRANSMISSION

MECP2 依赖性转录抑制

基本信息

批准号：
9779449
负责人：
LISA M MONTEGGIA
金额：
$ 22.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9779449
关键词：
MECP2 DEPENDENT TRANSCRIPTIONAL REPRESSION NEUROTRANSMISSION

项目摘要

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.

项目摘要在过去的〜5年中，我们研究了MECP2在神经传递中的作用转录因子影响基因表达。我们的数据表明MECP2是一个Bona 突触函数的FIDE调节剂在MECP2中具有双向变化，导致倒数神经传递的改变。我们还显示了小鼠MECP2表达的改变导致几种行为表型以及突触特定度量的缺陷可塑性进一步将MECP2视为突触过程的关键介体。一个在抑郁症领域令人惊讶的发现是证明scopolamine的证明，毒蕈碱乙酰胆碱受体拮抗剂具有快速和持久的抗抑郁药沮丧的人的回应。我们已经开始研究西孢胺的抗抑郁作用，并发现它取决于MECP2的表达这些效果在MECP2敲除小鼠中丧失。我们的发现还表明西cpollamine的抗抑郁作用取决于MECP2依赖性转录机制导致BDNF表达增加，这对于行为效应很重要。我们的初步数据进一步表明，东pol碱会触发MECP2磷酸化。丝氨酸421（PMECP2），已证明可以调节BDNF表达。初始实验，我们发现西cpol虫通过毒蕈碱M1受体的阻断起作用触发PMECP2。这笔赠款的目的是探讨MECP2-的新假设依赖的转录机制是快速起作用抗抑郁作用的基础 scopolamine。我们将使用艺术行为状态以及细胞和生化检验我们的假设的方法。总的来说，这些研究将有助于更好了解快速作用抗抑郁反应的基础机制以及提供有关MECP2调节作为治疗靶点的新见解。