A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity

主要调查员：陈露 摘要 我们的研究重点是揭示一种非Hebbian突触的分子机制 可塑性，即稳态突触可塑性。与Hebbian可塑性的自我强化性质不同， 动态平衡可塑性在不同的规则下运行，作为防止Hebbian失控的“纠正”机制 可塑性。与Hebbian可塑性相比，动态平衡的分子和细胞机制 突触的可塑性还知之甚少，它们在神经精神障碍中的作用在很大程度上是 未被开发的。我们实验室在过去几年的工作表明，维甲酸(RA)信号是一种主要的信号 介导动态平衡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。此外，我们还证明了 在更自然、更丰富的环境下，成年小鼠的自稳突触可塑性受到损害 诱发失控的Hebbian塑性，表现为LTP显著增强，LTD减小。作为一名 行为后果：体内平衡可塑性缺陷的动物表现出学习能力增强但减少 在丰富的环境中成长时的行为灵活性。我们的工作共同建立了一种联系 突触RA信号、内稳态可塑性和认知功能，并提示内稳态受损 可塑性可能是FXS认知缺陷的原因之一。所提议的研究项目的目标是进一步获得 了解RA依赖的动态平衡可塑性的分子和细胞机制。具体来说， 在稳态突触可塑性的背景下，我们将关注RA信号的三个方面：跨突触 细胞黏附分子Neurexins、BDNF-TrkB逆行信号转导及细胞间功能相互作用 FMRP和RA受体RARα。总之，这项拟议研究的结果将确定新的候选分子 研究体内内稳态突触可塑性功能的工具，也为发现 治疗FXS和潜在的其他精神障碍的新药物靶点。 相关性 该项目将研究突触RA信号调节突触的分子机制 以动态平衡的方式增强力量。利用FXS模型小鼠和人类FXS患者神经元的最新研究 确定RA依赖的稳态突触可塑性缺陷是突触功能障碍的主要表型 与脆性X综合征有关。因此，发现更多关键参与其中的分子成员 体内平衡可塑性将为发现治疗FXS和其他形式的新药靶点提供机会 一种精神疾病，其主要原因是体内平衡可塑性受损导致的回路适应不良 到疾病症状。 PHS 398/2590(11/07版)第1页摘要

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