The roles of FMRP in cortical development

脆性X综合征是最常见的精神发育迟滞形式，可以从一个人身上遗传？父母。这是由于缺乏一种名为脆性X智力低下蛋白或FMRP的蛋白质引起的。脆性X综合征的许多严重认知症状与大脑皮层的异常组织有关，大脑皮层是大脑中主要负责调节有意识的感觉体验、思想和行动的区域。由于脆性X综合征的症状最早出现在儿童发育期间，因此确定FMRP如何影响大脑发育很可能有助于更好地了解脆性X综合征，并可能建议新的或改进的治疗方法。然而，尽管大多数关于FMRP的科学研究都集中在它在成人中的作用，但很少有人关注FMRP在大脑皮层发育中的作用。我们建议通过确定FMRP在大脑皮层不同发育阶段的哪里发现FMRP，并确定FMRP的移除如何影响大脑皮层的发育和组织来解决这个问题。到目前为止，为设计脆性X综合征的治疗而建立的最有希望的框架是基于最近的一项理论，该理论认为FMRP通过改变神经递质受体mGluR的功能来限制神经元的交流。我们研究的第二部分将集中在FMRP和mGluRs在发育过程中如何相互作用。我们将进行实验，以确定FMRP和mGluR5在发育过程中是否相互作用，并确定这些相互作用是否支持脆性X综合征的mGluR理论。由于支撑大脑皮层组织发育的遗传因素才刚刚开始建立，阐明FMRP在这些过程中的作用将对理解大脑皮层发育所涉及的机制做出重大贡献。此外，我们的实验将为脆性X患者大脑功能改变的细胞机制提供基本的见解，因此可能对发现治疗精神发育迟缓的新疗法很重要。

Fragile X syndrome is the most common form of mental retardation that can be inherited from ones? parents. It is caused by the absence of a single protein called the fragile X mental retardation protein or FMRP. Many of the severe cognitive symptoms of fragile X are associated with abnormal organization of the cerebral cortex, the region of the brain that is primarily responsible for mediating conscious sensory experiences, thoughts and actions.Since the symptoms of fragile X syndrome first appear during childhood development it is likely that establishing how FMRP influences development of the brain will lead to a better understanding of fragile X syndrome and may suggest new or improved treatments. However, while most scientific investigations of FMRP have focused on its role in adults, very little attention has been given to the role of FMRP in the development of the cerebral cortex. We propose to address this issue by establishing where in the cerebral cortex FMRP is found during different stages of development and by determining how removal of FMRP, as occurs in FXS, influences the development and organization of the cerebral cortex.The most promising framework established so far for designing treatments for fragile X syndrome is based on a recent theory which suggests that FMRP restricts neuronal communication by altering the function of a neurotransmitter receptor, called mGluR. The second part of our study will focus on how FMRP and mGluRs interact during development. We will carry out experiments that will establish if FMRP and mGluR5 interact during development and will determine if these interactions support the mGluR theory of fragile X syndrome.Since the genetic factors that underlie the organizational development of the cerebral cortex are only beginning to be established, elucidation of the roles of FMRP in these processes will represent a significant contribution to understanding the mechanisms involved in development of the cerebral cortex. Moreover, our experiments will provide fundamental insights into the cellular mechanisms through which the altered brain function in fragile X patients arise and therefore may be important for discovery of new therapeutic treatments for mental retardation.