权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MeCP2 Dependent Transcriptional Repression & Neurotransmission

MeCP2 依赖性转录抑制

基本信息

批准号：
10462209
负责人：
LISA M MONTEGGIA
金额：
$ 39.61万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462209
关键词：
Acute Antidepressive Agents Behavior Behavioral Biochemical Brain Brain-Derived Neurotrophic Factor Calcineurin Chemosensitization Chromatin Structure Data Depressed mood Electrophysiology (science)Equilibrium Gene Expression Genes Genetic Transcription Goals Grant Hippocampus (Brain)Histone Deacetylase Individual Instruction Ketamine Knock-in Mouse Link Long-Term Effects Maintenance MeCP2 Duplication Syndrome Measures Mediating Mediator of activation protein Mental Depression Methods Methyl-CpG-Binding Protein 2 Molecular Mus Muscle Cells Mutant Strains Mice NMDA receptor antagonist Neurons Optics Phosphorylation Process Regulation Repressor Proteins Rett Syndrome Rodent Role Serine Signal Transduction Slice Synapses Synaptic Transmission Synaptic plasticity Testing Transcriptional Regulation Vertebral column Work antidepressant effect behavioral phenotyping calmodulin-dependent protein kinase II drug action enhancing factor gain of function gene repression insight link protein loss of function mutation mouse model nervous system disorder neurotransmission novel response synaptic function therapeutic target transcription factor translational approach

项目摘要

PROJECT SUMMARY Over the past ~15 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 ketamine, an NMDA receptor antagonist, has rapid and long-lasting antidepressant responses in depressed individuals. We are investigating the mechanism of the antidepressant action of ketamine, and found that the sustained antidepressant effects are dependent on MeCP2 Ser421 phosphorylation. In contrast, the rapid antidepressant action of ketamine is not dependent on MeCP2 Ser421 phosphorylation, revealing a distinct mechanism between rapid and sustained effects. The objective of this grant is to explore the novel hypothesis that MeCP2- dependent transcriptional mechanisms underlie the sustained antidepressant effects of ketamine. 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 the maintenance of antidepressant effects as well as provide novel insight into MeCP2 regulation as a therapeutic target.

项目摘要在过去的15年里，我们研究了MeCP 2作为转录因子在神经传递中的作用影响基因表达。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相互改变。我们还显示小鼠中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进一步暗示MeCP 2是突触过程的关键介质。一在抑郁症领域，一个相当令人惊讶的发现是，氯胺酮，一种NMDA，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。我们研究氯胺酮抗抑郁作用的机制，发现持续的抗抑郁作用依赖于MeCP2 Ser421磷酸化。相反，快速氯胺酮的抗抑郁作用不依赖于MeCP2 Ser421磷酸化，揭示了一种独特的快速和持续效果之间的关系。这项资助的目的是探索新的假设 MeCP2依赖的转录机制是氯胺酮持续抗抑郁作用的基础。我们将使用最先进的行为以及细胞和生物化学方法来检查我们的假说.总的来说，这些研究将有助于更好地理解维持抗抑郁作用，并为MeCP2调节作为治疗药物提供新的见解目标

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation.

DOI：
10.1038/s41593-021-00868-8
发表时间：
2021-08
期刊：
Nature neuroscience
影响因子：
25
作者：
Kim JW;Autry AE;Na ES;Adachi M;Björkholm C;Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM

BDNF signaling in context: From synaptic regulation to psychiatric disorders.

DOI：
10.1016/j.cell.2021.12.003
发表时间：
2022-01-06
期刊：
Cell
影响因子：
64.5
作者：
Wang CS;Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM

Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function.

DOI：
10.1523/jneurosci.0097-09.2009
发表时间：
2009-06-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Akhtar MW;Raingo J;Nelson ED;Montgomery RL;Olson EN;Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM

A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission.

DOI：
10.1523/jneurosci.6000-11.2012
发表时间：
2012-02-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Na ES;Nelson ED;Adachi M;Autry AE;Mahgoub MA;Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM

Probing the segregation of evoked and spontaneous neurotransmission via photobleaching and recovery of a fluorescent glutamate sensor.

通过光漂白和恢复荧光谷氨酸传感器的诱发和自发神经传递的分离。