Project 2

项目摘要 我们的研究集中在揭示一种形式的分子机制和研究其功能影响 非Hebbian突触可塑性，即稳态突触可塑性。与自我强化的 Hebbian可塑性的本质，稳态可塑性在不同的规则下作为一种纠正机制来运行 防止希伯来的可塑性失控。与Hebbian可塑性相比，体内平衡缺陷的贡献 神经发育障碍中突触对神经元和行为表型的可塑性实际上是 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 诱导失控的Hebbian可塑性，表现为显著增强的长时程增强(LTP)和 减轻长期抑郁(LTD)。作为行为后果，体内平衡缺陷的动物 当在丰富的环境中长大时，可塑性表现出增强的学习能力，但降低了行为灵活性。 总之，我们的工作在突触类风湿因子信号、稳态可塑性和认知之间建立了联系 功能，提示体内平衡可塑性受损可能是FXS认知缺陷的原因之一。目标是 建议的研究项目的目的是在这个知识库的基础上，建立一个疾病研究平台 从中可以识别在细胞和突触水平上翻译相关的FXS表型，以及它们的 在行为水平上的认知功能中的功能暗示可以在模式生物中进一步探索。至 为了实现这一点，我们将使用小鼠FXS模型和由人FXS生成的人脑器官 患者细胞，在分子和细胞水平上进行平行实验，并确定 这两个模型系统。然后，我们将探索这些共同表型对学习和记忆的影响 在表现FXS的小鼠中形成，从而进一步深入了解内稳态突触可塑性如何改变 人类患者的认知功能受损。建立这样一个疾病研究平台将有助于 以动物模型为基础的药物发现，专注于治疗与人类患者相关的表型。

Project Summary Our research focuses on uncovering the molecular mechanisms and investigating the functional impact 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 contribution of defective homeostatic synaptic plasticity to neuronal and behavioral phenotypes in neurodevelopmental disorders is virtually 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 long-term potentiation (LTP) and diminished long-term depression (LTD). As a behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced behavioral flexibility when raised in an 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 build upon this knowledge base, and establish a disease research platform from which translationally relevant FXS phenotypes at cellular and synaptic levels can be identified and their functional implication in cognitive function at behavioral level can be further explored in model organisms. To achieve this, we will use both a mouse FXS model and human cerebral organoids generated from human FXS patient cells, run parallel experiments at molecular and cellular levels, and identify shared phenotypes between the two model systems. We will then explore the impact of these shared phenotypes on learning and memory formation in behaving FXS mice, thus gaining further insight into how altered homeostatic synaptic plasticity may compromise cognitive function in human patients. Establishing such a platform for disease research will facilitate animal model-based drug discovery by focusing on treatment of phenotypes that are pertinent to human patients.