A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity

首席研究员：陈璐 总结 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 可塑性。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 未经探索。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。此外，我们证明 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 减小。作为一个 行为后果，具有缺陷稳态可塑性的动物表现出学习能力增强，但学习能力下降 在丰富的环境中长大时的行为灵活性。我们的工作共同在之间建立了联系 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。拟议研究项目的目标是进一步获得 了解 RA 依赖性稳态可塑性的分子和细胞机制。具体来说， 我们将重点关注稳态突触可塑性背景下 RA 信号传导的三个方面：跨突触 细胞粘附分子神经毒素、BDNF-TrkB 逆行信号传导以及两者之间的功能相互作用 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 研究稳态突触可塑性的体内功能的工具，并提供发现的见解 治疗 FXS 和其他潜在精神障碍的新药物靶点。 相关性 该项目将研究突触 RA 信号传导调节突触的分子机制 以稳态方式增强力量。最近使用 FXS 模型小鼠和人类 FXS 患者神经元进行的研究 确定 RA 依赖性稳态突触可塑性缺陷是主要的突触功能障碍表型 与脆性X综合征有关。因此，发现了其他关键参与的分子参与者 稳态可塑性将为发现治疗 FXS 和其他形式的新药物靶点提供机会 因稳态可塑性受损而导致的神经回路适应不良是精神疾病的主要原因 到疾病症状。 PHS 398/2590（修订版 11/07） 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