MeCP2 Dependent Transcriptional Repression & Neurotransmission

MeCP2 依赖性转录抑制

• 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
• 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

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年中，我们研究了MECP2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器 随着MECP2的双向变化，导致神经传递的相互改变。我们也有 在小鼠中显示MECP2表达的改变会导致几种行为表型以及缺陷 突触可塑性的特定度量进一步将MECP2作为突触过程的关键介体。一个 在抑郁症领域中相当令人惊讶的发现是氯胺酮，NMDA 受体拮抗剂，在抑郁的个体中具有快速和持久的抗抑郁反应。我们是 研究氯胺酮抗抑郁作用的机制，发现持续 抗抑郁作用取决于MECP2 Ser421磷酸化。相反，迅速 氯胺酮的抗抑郁作用不依赖于Mecp2 Ser421磷酸化，揭示了一个独特的 快速和持续作用之间的机制。这笔赠款的目的是探索新颖的假设 MECP2依赖性的转录机制是氯胺酮持续抗抑郁作用的基础。 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 假设。总的来说，这些研究将有助于更好地理解该机制 维持抗抑郁药的作用，并提供对MECP2调节的新见解 目标。

项目成果

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
• 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
• 作者: Na ES;Nelson ED;Adachi M;Autry AE;Mahgoub MA;Kavalali ET;Monteggia LM
• 通讯作者: Monteggia LM

Loss of histone deacetylase 2 improves working memory and accelerates extinction learning.

• DOI: 10.1523/jneurosci.1001-12.2013
• 发表时间: 2013-04-10
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Morris MJ;Mahgoub M;Na ES;Pranav H;Monteggia LM
• 通讯作者: Monteggia LM