Antidepressants and Intracellular Signaling Linked to BDNF
抗抑郁药和与 BDNF 相关的细胞内信号传导
基本信息
- 批准号:8120484
- 负责人:
- 金额:$ 39.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-07-01 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffinityAgreementAnimal ModelAntidepressive AgentsBehavioralBehavioral ModelBrainBrain-Derived Neurotrophic FactorCellsDataDepressed moodDevelopmentFamilyGene TransferGenetic TranscriptionGlutamatesGrantHippocampus (Brain)In VitroIndividualKetamineKnock-outKnockout MiceLinkMK801MediatingMediator of activation proteinMental DepressionMessenger RNAModelingMolecularMusNerve Growth FactorsNeuronal PlasticityNeuronsNeurotrophic Tyrosine Kinase Receptor Type 2Peptide Elongation Factor 2PhosphorylationProsencephalonProteinsReceptor ActivationRegulationRepressionRestRoleSignal PathwaySignal TransductionTranslational RepressionTranslationsViralWorkaspartate receptorbasecalmodulin-dependent protein kinase IIIclinically relevantinhibitor/antagonistkinase inhibitormRNA Expressionmemberneurotrophic factornovelprotein expressionreceptorresearch studyresponse
项目摘要
ABSTRACT
Brain-derived neurotrophic factor (BDNF) is the most prevalent neurotrophin in brain; via actions on its high
affinity trkB receptor it enhances the survival of many types of central neurons and is implicated in several
forms of neural plasticity in the brain. Recent work suggests that endogenous BDNF in the hippocampus may
be involved in mediating antidepressant responses, in depression models in mice. A rather surprising finding in
the field of depression has been the demonstration that ketamine, an ionotropic glutamatergic n-methyl-daspartate
(NMDA) receptor antagonist, has rapid and long-lasting antidepressant effects in depressed
individuals. We have started to investigate the mechanisms of the antidepressant activity of ketamine,
specifically the potential involvement of endogenous BDNF in the hippocampus. In preliminary experiments,
we find that the NMDA receptor antagonists, ketamine, MK801 or CPP, produce fast-acting antidepressant
behavioral effects in depression models in mice. The fast acting antidepressant effects of ketamine occurs via
a BDNF dependent manner because these effects are lost in forebrain specific BDNF knockout mice. Our
findings also suggest that the antidepressant effects of ketamine require protein translation, but not
transcription, resulting in increases in BDNF protein levels that are important for the behavioral effect. Recent
work has suggested a strong causal link between blockade of resting NMDA receptor activation and rapid
increases in local dendritic protein translation. In agreement with recent in vitro work, we find that ketamine
causes a decrease in phosphorylation of eukaryotic elongation factor 2 (eEF2), which normally impedes
translation in its phosphorylated state, suggesting translational de-repression of BDNF mRNA. Importantly, we
provide preliminary evidence that inhibitors of the eEF2 kinase (also called CaMKIII) that normally
phosphorylates eEF2 trigger a fast-acting antidepressant-like effect in depression models in mice. These
findings suggest a behavioral and clinically relevant correlate of dendritic translational de-repression by NMDA
receptors. The objective of this grant is to link the regulation of translational repression to the effects of
antidepressants. Collectively, these studies promise to provide fundamentally novel information concerning
how endogenous BDNF in the hippocampus is involved in the fast acting antidepressant response of ketamine
and offer new leads toward the development of faster acting antidepressants.
摘要
脑源性神经营养因子(BDNF)是脑内最常见的神经营养因子,通过其高表达的神经营养因子,
它增强许多类型的中枢神经元的存活,并与几种神经元的存活有关。
大脑中神经可塑性的形式。最近的研究表明,海马体中的内源性BDNF可能
参与介导抗抑郁反应,在小鼠抑郁模型中。一个相当令人惊讶的发现,
抑郁症领域已经证明,氯胺酮,一种离子型阿片类药物能N-甲基-D-天冬氨酸,
(NMDA)受体拮抗剂,具有快速和持久的抗抑郁作用,
个体我们已经开始研究氯胺酮抗抑郁活性的机制,
特别是内源性BDNF在海马中的潜在参与。在初步实验中,
我们发现NMDA受体拮抗剂氯胺酮、MK 801或CPP产生快速作用的抗抑郁药,
对小鼠抑郁模型的行为影响。氯胺酮的快速抗抑郁作用是通过
这是因为这些作用在前脑特异性BDNF敲除小鼠中丧失。我们
研究结果还表明,氯胺酮的抗抑郁作用需要蛋白质翻译,
转录,导致BDNF蛋白水平的增加,这对行为效应很重要。最近
研究表明,阻断静息NMDA受体活化与快速的
局部树突状蛋白翻译增加。与最近的体外研究一致,我们发现氯胺酮
导致真核细胞延伸因子2(eEF 2)磷酸化水平降低,
在其磷酸化状态下的翻译,表明BDNF mRNA的翻译去抑制。重要的是我们
提供了初步的证据,表明正常情况下的eEF 2激酶(也称为CaMK III)抑制剂,
磷酸化eEF 2在小鼠抑郁模型中触发快速作用的抗抑郁剂样作用。这些
研究结果表明,行为和临床相关的树突翻译去抑制NMDA
受体。这项资助的目的是将翻译抑制的调节与以下因素的影响联系起来:
抗抑郁药总的来说,这些研究有望提供有关以下方面的基本新颖信息:
海马中内源性BDNF如何参与氯胺酮的快速抗抑郁反应
并为开发更快起效的抗抑郁药提供了新的线索。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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{{ truncateString('LISA M MONTEGGIA', 18)}}的其他基金
ANTIDEPRESSANTS & INTRACELLULAR SIGNALING LINKED TO BDNF
抗抑郁药
- 批准号:
9919639 - 财政年份:2018
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
10462209 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
8913777 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
8213471 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
7620054 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
8018665 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
8744305 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MECP2 DEPENDENT TRANSCRIPTIONAL REPRESSION & NEUROTRANSMISSION
MECP2 依赖性转录抑制
- 批准号:
9779449 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
7769456 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
MeCP2 Dependent Transcriptional Repression & Neurotransmission
MeCP2 依赖性转录抑制
- 批准号:
8658621 - 财政年份:2008
- 资助金额:
$ 39.23万 - 项目类别:
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