The roles of FMRP in cortical development

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.

Fragile X syndrome (FXS) is the most common genetically inherited form of mental retardation. It results from the loss of a single protein, the fragile X mental retardation protein, FMRP. The mechanisms through which the absence of FMRP leads to the symptoms of FXS are not understood. Many of the cognitive and behavioural impairments found in fragile X individuals are associated with abnormal organization of the cerebral cortex. Although FXS is a disorder that emerges during childhood development, most experimental studies have focused on the functions of FMRP in the mature nervous system and little is known about the developmental roles of FMRP. Currently the most promising framework for designing treatments for FXS-associated symptoms is based on a hypothesis that suggests that FMRP acts to restrict signaling through group 1 metabotropic glutamate receptors (mGluRs). However, whether FMRP and group I mGluRs interact to control the development and organization of the cerebral cortex is not known.
We propose to test the hypothesis that failure of FMRP signaling during development leads to abnormal cortical organization and that a key developmental function of FMRP is to constrain processes driven by group 1 mGluR signaling. We will focus on the development of the primary somatosensory cortex, as this region is an excellent model system for the study of cortical development. To determine the developmental profile of FMRP expression in primary somatosensory cortex and the time points when altered cortical organization due to impaired FMRP signaling become apparent, we will apply state of the art techniques to analyse somatosensory cortex organisation during development in wild-type mice and in mice lacking Fmr1, the gene encoding FMRP. To establish if FMRP and mGluR5 signaling pathways interact during development and to determine whether these interactions support the mGluR theory of FXS, we will perform analysis of cortical organisation in mice lacking both Fmr1 and mGluR5, the predominant group 1 mGluR in the developing somatosensory cortex.
Since the genetic factors that underlie experience-dependent organization and refinement of cortical structures are only beginning to be established, elucidation of the role of FMRP in these processes will represent a significant contribution to understanding the mechanisms involved in cortical development. Moreover, the results of our experiments are likely to provide fundamental insights into the cellular mechanisms through which cognitive symptoms of FXS arise and may be important for discovery of new therapies for mental retardation.