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 突触传递及其可塑性是基于一组核心的突触受体， 神经递质如谷氨酸和GABA。神经营养因子，如脑源性神经营养因子 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诱导 以及突触可塑性的表达。尽管神经递质和神经营养因子信号是大多数 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，很少有人知道这些不同的受体类如何工作， 通过直接和间接形式的串扰进行协调。由于缺乏直接测试， 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（mGluR 5）能够在两种天然的谷氨酸受体中相互调节。 异源系统。与以前的研究相比，这些研究集中在GPCR激活的能力上， 在RTK信号传导中，我们已经鉴定了RTK（TrkB）接合GPCR（mGluR 5）的第一个实例之一，作为一种新的GPCR（mGluR 5）。 信号效应子在本提案中，我们将检验mGluR 5是TrkB效应的关键介质的假设 通过放大和改变下游信号传导到典型效应子的时空动态， 一种独特的依赖于串扰的突触可塑性。总的来说，这种新形式的TrkB-mGluR 5信号传导 可能有助于与神经可塑性相关的各种高级神经系统功能， 这归因于BDNF-TrkB神经营养因子系统。目的1：明确BDNF-TrkB受体介导的信号转导 与mGluR 5的串扰。目的2将破译调节TrkB/mGluR 5串扰的信号传导机制。目的 3将确定TrkB-mGluR 5协同作用对BDNF-LTP和mGluR 5-LTD的影响。