Project 2

项目摘要 我们的研究重点是揭示分子机制并研究形式的功能影响 非Hebbian突触可塑性，即稳态突触可塑性。与自我强化相反， 赫布可塑性的本质，稳态可塑性在不同的规则下运作，作为一种“纠正”机制， 防止赫布可塑性失控。与赫布可塑性相比， 神经发育障碍中神经元和行为表型的突触可塑性实际上 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，表现为大大增强的长时程增强（LTP）， 减少长期抑郁症（LTD）。作为一种行为后果， 可塑性在丰富的环境中长大时，表现出增强的学习能力，但降低了行为的灵活性。 总之，我们的工作建立了突触RA信号，稳态可塑性和认知之间的联系。 功能，并表明受损的稳态可塑性可能有助于FXS的认知缺陷。目标 建议研究项目的一个主要目标是建立一个疾病研究平台， 从中可以鉴定细胞和突触水平上的病理相关FXS表型， 行为水平上认知功能的功能含义可以在模式生物中进一步探索。到 为了实现这一点，我们将使用小鼠FXS模型和由人FXS产生的人脑类器官 患者细胞，在分子和细胞水平上进行平行实验，并确定 两个模型系统。然后我们将探讨这些共同的表型对学习和记忆的影响 形成的行为FXS小鼠，从而获得进一步了解如何改变稳态突触可塑性， 损害人类患者的认知功能。建立这样一个疾病研究平台将有助于 基于动物模型的药物发现，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.