MeCP2 Dependent Transcriptional Repression & Neurotransmission

MeCP2 依赖性转录抑制

基本信息

批准号：
8913777
负责人：
LISA M MONTEGGIA
金额：
$ 39.75万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913777
关键词：
Acute Animal Model Antidepressive Agents Behavior Behavioral Biochemical Brain Brain-Derived Neurotrophic Factor Cells Chromatin Complex Data Depressed mood Development Funding Gene Expression Gene Targeting Genetic Transcription Goals Grant Health Histones Individual Knockout Mice Light Link Measures Mediating Mediator of activation protein Mental Depression Methyl-CpG-Binding Protein 2 Molecular Mus Muscarinic Acetylcholine Receptor Muscarinic M1 Receptor Muscle Cells Neurodevelopmental Disorder Neurons Pathway interactions Phenotype Phosphorylation Play Process Protein Kinase Psychotropic Drugs Regulation Resistance Rett Syndrome Role Scopolamine Serine Signal Pathway Slice Synapses Synaptic Transmission Synaptic plasticity Syndrome Therapeutic Agents Transcriptional Regulation Work base behavioral response depressed patient enhancing factor follow-up gain of function gene repression human CHRM1 protein insight link protein loss of function mutation neurotransmission novel research study response synaptic function therapeutic target

项目摘要

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.

描述（由申请人提供）：在过去〜5年中，我们研究了MECP2在神经传递中的作用，作为影响基因表达的转录因子。我们的数据显示，MECP2是突触功能的真正调节剂，MECP2的双向变化导致神经传递的相互改变。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可塑性的特定测量方法的缺陷，进一步将MECP2作为突触过程的关键介体。在抑郁症领域的一个相当令人惊讶的发现是，毒蕈碱乙酰胆碱受体拮抗剂的scopolamine的证明是在抑郁个体中具有快速而持久的抗抑郁反应。我们已经开始研究Scopolamine抗抑郁作用的机理，并发现它取决于MECP2的表达，因为这些作用在MECP2敲除小鼠中丢失。我们的发现还表明，西孢胺的抗抑郁作用取决于MECP2依赖性的转录机制，从而导致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，Scopolamine在丝氨酸421（PMECP2）处触发MECP2磷酸化，该磷酸化已被证明调节BDNF表达。在最初的实验中，我们发现Scopolamine通过阻断毒蕈碱M1受体的封锁来触发PMECP2。这项赠款的目的是探索新的假设，即MECP2依赖性转录机制是旁皮胺的快速起作用抗抑郁作用的基础。我们将使用艺术行为的状态以及细胞和生化方法来检查我们的假设。总的来说，这些研究将有助于更好地理解快速作用抗抑郁反应的基础机制，并为MECP2调节作为治疗靶靶标提供新的见解。