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: 10710401
• 负责人: Francis Sang Yong Lee
• 金额: $ 54.25万
• 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/10710401
• 关键词: Acute; Antidepressive Agents; Attention; Attenuated; Binding; Binding Proteins; Biological Assay; Biosensor; Brain; Brain-Derived Neurotrophic Factor; Calcium; Cells; Central Nervous System; Complex; Data; Dendrites; Development; Electrophysiology (science); Event; Family; Family member; Fluoxetine; Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Glutamates; Growth Factor; Guanine; Guanine Nucleotide Exchange Factors; Hippocampus; Ion Channel; Ketamine; Knockout Mice; Long-Term Depression; Long-Term Potentiation; Mediating; Mediator; Metabotropic Glutamate Receptors; Molecular; Nerve Growth Factor Receptors; Nervous System Physiology; Neurodegenerative Disorders; Neuromodulator; Neuronal Plasticity; Neurons; Neuropeptides; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 2; Output; Pathway interactions; Pharmacology; Phosphotransferases; Physiological; Property; Protein Secretion; Receptor Protein-Tyrosine Kinases; Role; Series; Shapes; Signal Transduction; Slice; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; System; Testing; Time; Work; antidepressant effect; desensitization; extracellular; fluorescence imaging; gamma-Aminobutyric Acid; genetic manipulation; metabotropic glutamate receptor 5; neuronal circuitry; neuropsychiatric disorder; neurotrophic factor; novel; optogenetics; postsynaptic; 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.

项目概要 突触传递及其可塑性基于一组快速感知的突触受体核心 神经递质如谷氨酸和 GABA。神经营养因子，例如脑源性神经营养因子 （BDNF），通常被认为在较慢的时间尺度上发出信号，但也被证明可以调节感应 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是大多数 突触可塑性的形式并作为病理生理学和治疗的主要介质 神经生成和神经精神疾病，人们对这些不同受体类别如何发挥作用知之甚少 通过直接和间接形式的串扰来协调一致。由于缺乏直接测试 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) 能够在两种天然状态下相互调节 和异源系统。与之前的研究相比，之前的研究重点关注 GPCR 激活的能力 RTK 信号传导，我们已经确定了 RTK (TrkB) 与 GPCR (mGluR5) 接合的第一个例子之一 信号效应器。在本提案中，我们将检验 mGluR5 是 TrkB 效应的关键调节因子的假设 通过放大和改变下游信号传递给典型效应器的时空动力学来驱动 一种独特形式的串扰依赖性突触可塑性。总的来说，这种新形式的 TrkB-mGluR5 信号传导 可能有助于与神经可塑性相关的多种高级神经系统功能 归因于 BDNF-TrkB 神经营养蛋白系统。目标 1 将定义 BDNF-TrkB 受体介导的信号传导 与 mGluR5 的串扰。目标 2 将破译调节 TrkB/mGluR5 串扰的信号机制。目的 图3将确定TrkB-mGluR5协同作用对BDNF-LTP和mGluR5-LTD的影响。