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。在父母的建议研究项目的目标 格兰特的目的是进一步了解RA依赖性稳态的分子和细胞机制， 小鼠大脑的可塑性。本行政补编中提议的项目进一步扩大了 人类神经元的实验系统。具体地说，我们将研究是否异常的选择性剪接， Neurexin基因是FXS中稳态突触可塑性表型的基础。利用人脑类器官 和我们实验室建立的类胶质细胞模型，我们的目标是在人类神经元中验证特异性 小鼠研究的目标1。 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 in the parent grant is to gain further understanding of the molecular and cellular mechanisms of RA-dependent homeostatic plasticity in the mouse brain. The project proposed in this administrative supplement further extends the experimental system to human neurons. Specifically, we will investigate whether aberrant alternative splicing of Neurexin genes underlies homeostatic synaptic plasticity phenotype in the FXS. Using the human brain organoid and assembloid models established in our lab, we will aim to validate in human neurons the findings from Specific Aim 1 of the mouse studies. PHS 398/2590 (Rev. 11/07) Page 1 Summary