A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity

视黄酸依赖性稳态突触可塑性的分子研究

基本信息

批准号：
10613502
负责人：
Lu Chen
金额：
$ 54.22万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613502
关键词：
AMPA Receptors Address Adult Affect Animals Behavioral Binding Brain-Derived Neurotrophic Factor Cell Adhesion Molecules Cognitive deficits Coupled Data Development Disease Drug Targeting Event Excitatory Synapse Exhibits FMRP Fragile X Syndrome Functional disorder Funding Opportunities Genetic Genetic Transcription Goals Hippocampus Human Impairment Inherited Inhibitory Synapse Intellectual functioning disability Investigation Laboratories Learning Link Mediating Mental disorders Modeling Molecular Mus Mutation Nature Neurons Neurosciences Patients Phenotype Physiological Principal Investigator Process Proteins RNA Splicing Regulation Research Research Project Grants Retinoic Acid Receptor Role Runaway Running Sensory Series Shapes Signal Pathway Signal Transduction Structure Symptoms Synapses Synaptic plasticity Testing Translations Tretinoin Variant Work cognitive function environmental enrichment for laboratory animals flexibility in vivo insight mouse model nervous system disorder neural circuit neuropsychiatric disorder new therapeutic target novel postsynaptic presynaptic prevent response retinoic acid receptor alpha synaptic function tool trafficking

项目摘要

Principal Investigator: Chen, Lu Summary Our research focuses on uncovering the molecular mechanisms of a form of non-Hebbian synaptic plasticity, namely homeostatic synaptic plasticity. In contrast to the self-reinforcing nature of Hebbian plasticity, homeostatic plasticity operates under different rules as a “corrective” mechanism to prevent run-away Hebbian plasticity. Compared to Hebbian plasticity, the molecular and cellular mechanisms underlying homeostatic synaptic plasticity is much less understood, and their implication in neuropsychiatric disorders is largely unexplored. Work from our labs in the past years show that retinoic acid (RA) signaling, a major signaling pathway mediating homeostatic synaptic plasticity, is severely impaired in the absence of FMRP expression, resulting in a lack of homeostatic plasticity in both mouse and human FXS neurons. Moreover, we demonstrate that under a more natural, enriched environment, compromised homeostatic synaptic plasticity in adult mice induces run away Hebbian plasticity as manifested by greatly enhanced LTP and diminished LTD. As a behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced behavioral flexibility when raised in enriched environment. Together, our work establishes a link between synaptic RA signaling, homeostatic plasticity and cognitive function, and suggests that impaired homeostatic plasticity may contribute to cognitive deficits in FXS. The goal of the proposed research project is to gain further understanding of the molecular and cellular mechanisms of RA-dependent homeostatic plasticity. Specifically, we will focus on three aspects of RA signaling in the context of homeostatic synaptic plasticity: the trans-synaptic cell adhesion molecule neurexins, the BDNF-TrkB retrograde signaling, and the functional interaction between FMRP and RA receptor RARα. Together, results from this proposed study will identify new candidate molecular tools for investigating in vivo function of homeostatic synaptic plasticity, and also provide insight into discovering new drug targets for treating FXS and potentially other mental disorders. Relevance This project will investigate molecular mechanisms through which synaptic RA signaling regulates synaptic strength in a homeostatic manner. Recent studies using FXS model mice and human FXS patient neurons establish that defective RA-dependent homeostatic synaptic plasticity is a major synaptic dysfunction phenotype associated with fragile-x syndrome. Thus, uncovering additional molecular players critically involved in homeostatic plasticity will provide the opportunity to discover new drug targets for treating FXS and other forms of mental illness in which circuit maladaptation due to compromised homeostatic plasticity is a major contributor to disease symptoms. PHS 398/2590 (Rev. 11/07) Page 1 Summary

首席研究员：陈，卢概括我们的研究重点是揭示一种非赫比亚突触形式的分子机制可塑性，即体内稳态可塑性。与Hebbian可塑性的自我增强性质相反，稳态可塑性在不同的规则下运行，作为防止逃亡Hebbian的“纠正”机制可塑性。与Hebbian可塑性相比，稳态的分子和细胞机制突触可塑性知之甚少，它们在神经精神疾病中的影响很大意外。过去几年我们实验室的工作表明视黄酸（RA）信号传导，这是一个主要信号传导介导稳态突触可塑性的途径在没有FMRP表达的情况下严重受损导致小鼠和人FXS神经元缺乏稳态可塑性。而且，我们证明了在更自然，丰富的环境下，成年小鼠的稳态可塑性受损诱导的Hebbian可塑性逃离了，这表现为LTP的大大增强和LTD的减少。作为行为后果，稳态可塑性有缺陷的动物暴露了增强的学习，但减少了在丰富的环境中提高行为灵活性。我们的工作共同建立了联系突触RA信号传导，稳态可塑性和认知功能，并表明稳态损害可塑性可能有助于FXS中的认知定义。拟议的研究项目的目标是进一步获取了解RA依赖性稳态可塑性的分子和细胞机制。具体来说，我们将重点介绍在稳态突触可塑性的背景下RA信号传导的三个方面：反式突触细胞粘附分子神经氧素，BDNF-TRKB逆行信号传导和功能相互作用 FMRP和RA受体RARα。总之，这项拟议的研究的结果将确定新的候选分子调查体内稳态突触可塑性功能的工具，并提供有关发现的洞察力用于治疗FXS和可能其他精神障碍的新药物。关联该项目将研究突触RA信号传导调节突触的分子机制以稳态方式的力量。使用FXS模型小鼠和人FXS患者神经元的最新研究确定有缺陷的RA依赖性稳态突触可塑性是主要的突触功能障碍表型与脆弱的X综合征有关。那，发现其他分子玩家严格涉及稳态可塑性将为发现治疗FX和其他形式的新药物目标提供机会精神疾病，在这种疾病中，由于稳态可塑性受损而导致的电路疾病是主要因素的主要因素疾病症状。 PHS 398/2590（Rev. 11/07）第1页摘要