Regulation of Protein Translation and Depression by Cortical NMDA Receptors.

皮质 NMDA 受体对蛋白质翻译和抑制的调节。

基本信息

批准号：
8635390
负责人：
JEFFREY G TASKER
金额：
$ 22.1万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635390
关键词：
AMPA Receptors Animals Antidepressive Agents Behavior Behavioral Behavioral Assay Biological Cells Chemistry Complex Data Dendrites Depressed mood Disease model Dose Excision Experimental Models GTPase-Activating Proteins Generations Genes Genetic Glutamates Goals Immunofluorescence Immunologic Intervention Ketamine Knock-out Lead Measures Mediating Mental Depression Molecular Molecular Biology Monomeric GTP-Binding Proteins Mus N-Methyl-D-Aspartate Receptors Neurons Patients Pharmacologic Substance Pharmacology Play Prefrontal Cortex Protein Biosynthesis Proteins Ras homolog enriched in brain Receptor Signaling Regulation Reporter Resistance Role Signal Pathway Signal Transduction Sirolimus Slice Synapses Techniques Testing Translations aspartate receptor base calmodulin-dependent protein kinase II improved novel therapeutics public health relevance receptor function receptor-mediated signaling research study response synaptic function treatment-resistant depression voltage clamp

项目摘要

DESCRIPTION (provided by applicant): A single, low dose of the n-methyl d-aspartate receptor (NMDAR) antagonist ketamine produces rapid anti-depressant actions in treatment-resistant depressed patients. This observation strongly supports a role for cortical NMDAR function in depression, which could lead to the generation of new disease models and novel therapeutic strategies. While it is clear that NMDAR antagonism causes a rapid increase in protein translation in cortical neurons, the exact mechanisms underlying these incredible effects remain unclear. One critical unanswered question is how does suppression of NMDAR signaling promote protein translation? NMDARs are heteromultimeric complexes containing two GluN1 subunits and two GluN2 subunits, the latter of which are encoded by four genes (GluN2A-D). Cortical NMDARs are dominated by GluN2A and GluN2B subunits. Recent data have shown that GluN2B-containing NMDARs can act to directly suppress mammalian/mechanistic target of rapamycin (mTOR)-mediated protein translation in cortical neurons, through a cellular signaling mechanism that is uniquely associated with this subunit. Based upon these data, an exciting hypothesis is that relief of GluN2B-mediated suppression of mTOR signaling is responsible for producing the rapid anti- depressant effects observed in response to low dose ketamine treatment. The experiments in this proposal will test this hypothesis with the goal of improving our understanding of the cellular signaling pathways associated with cortical GluN2B-containing NMDARs and determining their involvement in depression.

描述（由申请人提供）：单次低剂量的 n-甲基 d-天冬氨酸受体 (NMDAR) 拮抗剂氯胺酮对难治性抑郁症患者产生快速抗抑郁作用。这一观察结果有力地支持了皮质 NMDAR 功能在抑郁症中的作用，这可能导致新的疾病模型和新的治疗策略的产生。虽然很明显 NMDAR 拮抗作用会导致皮质神经元中蛋白质翻译的快速增加，但这些令人难以置信的作用背后的确切机制仍不清楚。一个尚未解答的关键问题是 NMDAR 信号传导的抑制如何促进蛋白质翻译？ NMDAR 是包含两个 GluN1 亚基和两个 GluN2 亚基的异多聚体复合物，后者由四个基因 (GluN2A-D) 编码。皮质 NMDAR 以 GluN2A 和 GluN2B 亚基为主。最近的数据表明，含有 GluN2B 的 NMDAR 可以通过与该亚基独特相关的细胞信号传导机制，直接抑制哺乳动物/雷帕霉素靶点 (mTOR) 介导的皮质神经元蛋白翻译。基于这些数据，一个令人兴奋的假设是，缓解 GluN2B 介导的 mTOR 信号传导抑制是产生低剂量氯胺酮治疗反应中观察到的快速抗抑郁作用的原因。本提案中的实验将检验这一假设，目的是提高我们对与皮质含 GluN2B NMDAR 相关的细胞信号通路的理解，并确定它们与抑郁症的关系。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Two cellular hypotheses explaining the initiation of ketamine's antidepressant actions: Direct inhibition and disinhibition.

解释氯胺酮抗抑郁作用启动的两种细胞假说：直接抑制和去抑制。

DOI：
发表时间：
2016-01
期刊：
影响因子：
4.7
作者：
Miller, Oliver H;Moran, Jacqueline T;Hall, Benjamin J
通讯作者：
Hall, Benjamin J

The transcription factor NeuroD2 coordinates synaptic innervation and cell intrinsic properties to control excitability of cortical pyramidal neurons.

转录因子 NeuroD2 协调突触神经支配和细胞内在特性，以控制皮质锥体神经元的兴奋性。

DOI：
发表时间：
2016-07-01
期刊：
影响因子：
0
作者：
Chen, Fading;Moran, Jacqueline T;Zhang, Yihui;Ates, Kristin M;Yu, Diankun;Schrader, Laura A;Das, Partha M;Jones, Frank E;Hall, Benjamin J
通讯作者：
Hall, Benjamin J

Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior.

丘脑皮质回路的突触调节控制抑郁相关行为。