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

• 批准号: 10841345
• 负责人: Lu Chen
• 金额: $ 8.94万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10841345
• 关键词: Administrative Supplement; Adult; Alternative Splicing; Animals; Behavioral; Brain; Cognitive deficits; Event; Exhibits; FMRP; Genes; Genetic; Goals; Hippocampus; Human; Impairment; Investigation; Learning; Link; Mediating; Mental disorders; Modeling; Molecular; Mus; Nature; Neurons; Organoids; Phenotype; Principal Investigator; Research; Research Project Grants; Runaway; Running; Signal Pathway; Signal Transduction; Synapses; Synaptic plasticity; System; Tretinoin; Work; cognitive function; environmental enrichment for laboratory animals; flexibility; neuropsychiatric disorder; parent grant; prevent; tool

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 in the parent grant is to gain further understanding of the molecular and cellular mechanisms of RA-dependent homeostatic plasticity in the mouse brain. The project proposed in this administrative supplement further extends the experimental system to human neurons. Specifically, we will investigate whether aberrant alternative splicing of Neurexin genes underlies homeostatic synaptic plasticity phenotype in the FXS. Using the human brain organoid and assembloid models established in our lab, we will aim to validate in human neurons the findings from Specific Aim 1 of the mouse studies. PHS 398/2590 (Rev. 11/07) Page 1 Summary

首席研究员：陈璐 概括 我们的研究重点是揭示一种非赫布突触形式的分子机制 可塑性，即稳态突触可塑性与赫布可塑性的自我强化性质相反， 稳态可塑性在不同的规则下运作，作为防止赫布失控的“纠正”机制 与赫布可塑性相比，稳态的分子和细胞机制。 突触可塑性的了解要少得多，其对神经精神疾病的影响很大程度上还不清楚 我们实验室过去几年的工作表明，视黄酸（RA）信号是一种主要的信号传导。 介导稳态突触可塑性的通路在缺乏 FMRP 表达的情况下严重受损， 导致小鼠和人类 FXS 神经元缺乏稳态可塑性。 在更自然、更丰富的环境下，成年小鼠的稳态突触可塑性受到损害 导致赫布可塑性失控，表现为 LTP 大大增强和 LTD 减少。 行为后果，具有缺陷的稳态可塑性的动物表现出学习能力增强，但学习能力下降 在丰富的环境中培养行为灵活性，我们的工作在两者之间建立了联系。 突触 RA 信号传导、稳态可塑性和认知功能，并表明稳态受损 可塑性可能会导致 FXS 的认知缺陷。 父母提出的研究项目的目标。 赠款旨在进一步了解 RA 依赖性稳态的分子和细胞机制 本行政补充中提出的项目进一步扩展了小鼠大脑的可塑性。 具体来说，我们将研究人类神经元的实验系统是否存在异常的选择性剪接。 Neurexin 基因是 FXS 中稳态突触可塑性表型的基础。 和我们实验室建立的组装模型，我们的目标是在人类神经元中验证特定的研究结果 小鼠研究的目标 1。 PHS 398/2590（修订版。11/07）第 1 页摘要