Molecular and synaptic mechanisms of neurotrophin-glutamate crosstalk

神经营养蛋白-谷氨酸串扰的分子和突触机制

• 批准号: 10586395
• 负责人: Francis Sang Yong Lee
• 金额: $ 60.29万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-28 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586395
• 关键词: Acute; Antidepressive Agents; Attention; Attenuated; Binding; Binding Proteins; Biological Assay; Biosensor; Brain; Brain-Derived Neurotrophic Factor; Calcium; Cells; Complex; Data; Dendrites; Development; Electrophysiology (science); Event; Family; Family member; Fluoxetine; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genetic; Glutamates; Growth Factor; Guanine; Guanine Nucleotide Exchange Factors; Hippocampus (Brain); Ion Channel; Ketamine; Knockout Mice; Long-Term Depression; Long-Term Potentiation; Mediating; Mediator of activation protein; Metabotropic Glutamate Receptors; Metaplasia; Molecular; Nerve Growth Factor Receptors; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neuromodulator; Neuronal Plasticity; Neurons; Neuropeptides; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 2; Output; Pathway interactions; Pharmacology; Phosphotransferases; Physiological; Property; Protein Kinase; Receptor Protein-Tyrosine Kinases; Role; Series; Shapes; Signal Transduction; Slice; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; System; Testing; Time; Work; antidepressant effect; base; desensitization; extracellular; fluorescence imaging; gamma-Aminobutyric Acid; genetic manipulation; metabotropic glutamate receptor 5; neuronal circuitry; neuropsychiatric disorder; neurotrophic factor; novel; optogenetics; receptor; receptor-mediated signaling; response; spatiotemporal; synergism; tool; trafficking; treatment strategy

PROJECT SUMMARY Synaptic transmission and its plasticity are based on a core group of synaptic receptors that rapidly sense neurotransmitters such as glutamate and GABA. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are typically thought to signal on slower time scales, but have also been shown to regulate the induction and expression of synaptic plasticity. Despite both neurotransmitter and neurotrophin signaling underlying most forms of synaptic plasticity and serving as major mediators of the pathophysiology and treatment of neurogenerative and neuropsychiatric disorders, little is known about how these different receptor classes work in concert through direct and indirect forms of crosstalk. Motivated by the paucity of direct tests of neurotrophin/neurotransmitter crosstalk, our preliminary studies have indicated that the neurotrophin receptor, TrkB, and metabotropic glutamate receptor 5 (mGluR5) are able to mutually regulate each other in both native and heterologous systems. In contrast to previous studies which have focused on the ability of GPCRs to activate RTK signaling, we have identified one of the first examples of an RTK (TrkB) engaging a GPCR (mGluR5) as a signaling effector. In this proposal, we will test the hypothesis that mGluR5 is a critical mediator of TrkB effects by amplifying and altering the spatiotemporal dynamics of downstream signaling to canonical effectors to drive a unique form of crosstalk-dependent synaptic plasticity. Collectively, this new form of TrkB-mGluR5 signaling may contribute to the diverse higher order nervous system functions related to neural plasticity that have been attributed to the BDNF-TrkB neurotrophin system. Aim 1 will define BDNF-TrkB receptor mediated signaling crosstalk with mGluR5. Aim 2 will decipher the signaling mechanisms that regulate TrkB/mGluR5 crosstalk. Aim 3 will determine the impact of TrkB-mGluR5 synergy on BDNF-LTP and mGluR5-LTD.

项目摘要 突触传播及其可塑性基于迅速感知的突触受体的核心群体 神经递质，例如谷氨酸和GABA。神经营养蛋白，例如脑衍生的神经营养因子 （BDNF）通常被认为是在较慢的时间尺度上发出信号，但也已证明可以调节诱导 和突触可塑性的表达。尽管神经递质和神经营养蛋白信号传导大多数都 突触可塑性的形式和作为病理生理学的主要介体和治疗 神经生成和神经精神疾病，这些不同的受体类别如何起作用，知之甚少 通过直接和间接形式的串扰。受到直接测试的动机 神经营养蛋白/神经递质串扰，我们的初步研究表明，神经营养蛋白受体， TRKB和代谢型谷氨酸受体5（MGLUR5）能够在两个天然中相互调节 和异源系统。与以前的研究相反，该研究集中于GPCR激活的能力 RTK信号传导，我们已经确定了RTK（TRKB）的第一个示例之一，将GPCR（MGLUR5）引入为A 信号效应子。在此提案中，我们将测试mglur5是TRKB效应的关键介体的假设 通过扩增和更改下游信号的时空动力学，向规范效应器驱动 串扰依赖性突触可塑性的独特形式。总体而言，这种新形式的TRKB-MGLUR5信号传导 可能会导致与神经可塑性有关的多样化的高阶神经系统功能 归因于BDNF-TRKB神经营养系统。 AIM 1将定义BDNF-TRKB受体介导的信号传导 与mglur5串扰。 AIM 2将破译调节TRKB/MGLUR5串扰的信号传导机制。目的 3将确定TRKB-MGLUR5协同作用对BDNF-LTP和MGLUR5-LTD的影响。