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.

项目总结 突触的传递及其可塑性是基于一组核心的突触受体，这些突触受体可以快速感觉到 神经递质，如谷氨酸和GABA。脑源性神经营养因子等神经营养因子 (BDNF)，通常被认为是在较慢的时间尺度上发出信号，但也被证明调节诱导 以及突触可塑性的表达。尽管大多数神经递质和神经营养因子信号 突触可塑性的形式及其作为病理生理学和治疗的主要介质 神经发生和神经精神障碍，对这些不同的受体类如何工作知之甚少 通过直接和间接的相声形式协调一致。其动机是缺乏直接测试 神经营养素/神经递质串扰，我们的初步研究表明，神经营养素受体， TrkB和代谢型谷氨酸受体5(MGluR5)在这两个基因中都能够相互调节 和异源系统。与以往侧重于GPCRs激活能力的研究不同 RTK信令，我们已经确定了RTK(TrkB)使用GPCR(MGluR5)作为 信号效应器。在这个提案中，我们将检验mGluR5是TrkB效应的关键中介这一假设 通过放大和改变下游信号的时空动力学，将信号传递给规范的效应器 一种独特的依赖串扰的突触可塑性。总而言之，这种新形式的TrkB-mGluR5信号 可能与与神经可塑性有关的各种高级神经系统功能有关 归因于BDNF-TrkB神经营养因子系统。AIM 1将定义BDNF-TrkB受体介导的信号转导 与mGluR5的串扰。目标2将破译调节TrkB/mGluR5串扰的信号机制。目标 3将确定TrkB-mGluR5协同对BDNF-LTP和mGluR5-Ltd.的影响。