A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity

主要研究者：陈陆 总结 我们的研究重点是揭示一种非Hebbian突触形式的分子机制， 可塑性，即稳态突触可塑性。与赫布塑性的自我强化性质相反， 内稳态可塑性在不同的规则下作为一种“纠正”机制来防止赫布失控 可塑性。与赫布可塑性相比， 突触可塑性的理解要少得多，它们在神经精神疾病中的意义在很大程度上是 未开发的我们实验室在过去几年的工作表明，维甲酸（RA）信号，一种主要的信号传导， 介导稳态突触可塑性的途径，在FMRP表达缺失时严重受损， 导致小鼠和人FXS神经元缺乏稳态可塑性。此外，我们证明 在一个更自然，更丰富的环境下，成年小鼠的稳态突触可塑性受损， 诱导失控的赫布可塑性，表现为大大增强LTP和减少LTD。 行为后果，有缺陷的稳态可塑性的动物表现出增强的学习，但减少 在丰富的环境中长大的行为灵活性。我们的工作共同建立了一种联系， 突触RA信号，稳态可塑性和认知功能，并表明受损的稳态 可塑性可能导致FXS中的认知缺陷。拟议研究项目的目标是进一步获得 了解RA依赖的稳态可塑性的分子和细胞机制。具体地说， 我们将集中在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neurexins，BDNF-TrkB逆行信号传导，以及 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 研究体内稳态突触可塑性功能的工具，也为发现 治疗FXS和其他潜在精神障碍的新药物靶点。 相关性 本项目将研究突触RA信号调节突触神经元的分子机制。 以一种自我平衡的方式。使用FXS模型小鼠和人FXS患者神经元的最新研究 建立缺陷RA依赖性稳态突触可塑性是主要的突触功能障碍表型 与脆性X综合征有关因此，发现更多的分子参与者， 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 在精神疾病中，由于稳态可塑性受损而导致的回路适应不良是主要原因 疾病症状。 PHS 398/2590（Rev. 11/07）第1页

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