Charles L. Cox - US grants

DESCRIPTION (provided by applicant): Fragile X Syndrome (FXS), the leading cause of inherited mental retardation and the largest identified genetic basis for autism spectrum disorders, results from the lack of functional FMRP. One of the major anatomical phenotypes of the disorder is an alteration in the number and shape of dendritic spines, through which neurons communicate. This synaptic phenotype is seen both in human patients and in the mouse model of FXS. In typical individuals, the production and selective removal (pruning) of these connections gives rise to the development of an organized brain-wiring diagram that is guided by experience and learning. Interestingly, abnormal dendritic spines have been found in most forms of mental retardation, including Rett's and Down's syndrome, as well as many other neurological conditions involving altered cognition. This finding suggests that either altered spines indicate an underlying connection failure, or alternatively, could themselves cause mental deficiencies, and evidence for both possibilities exists. Thus, there is enormous interest in understanding how spine abnormalities develop, whether they can be treated, and how they relate to the cognitive disturbances that they seem to embody. Since FXS is caused by the loss of function of a single gene, the mouse model is a powerful system with which to begin answering these questions. This project seeks to determine the underlying dynamics and structure of synaptic connections in FXS, and how they arise during development. By monitoring synapses in living animals using 2-photon microscopy, we will be able to 1) determine the ontogeny and dynamic processes that leads to synaptic abnormalities seen in FXS, and 2) assess the capacity for plasticity and potential for reversal of this system through intervention. Model therapeutic treatments proposed include AAV-virus mediated restoration of FMRP expression, as well as drug treatments including Lithium and specific metabotropic glutamate receptor antagonists. By reintroducing FMRP in both the adult and developing animal (through viral restoration), and comparing our findings with nearly ideal restoration using a genetic conditional knockON model, we will be able to determine how and when the phenotype arises and to what extent dynamic and structural phenotypes can be restored. Understanding the timing of FMRP's involvement will have significant implications for the development of treatments for FXS individuals, many of whom are not diagnosed until they have already missed important developmental milestones. On the other hand, determining the dynamic pattern of changes in spines after FMRP restoration (only possible by in vivo imaging) will have implications for comparing pharmacological and viral-mediated treatments, each of which may alter dendritic spines in different ways. Elucidating the basic mechanisms of neural development and plasticity is essential, not only for understanding the roles of FMRP but also for other disorders of the synapse that are likely to share similar fundamental mechanisms. PUBLIC HEALTH RELEVANCE: Fragile X syndrome (FXS) is the most common form of inherited mental retardation and one of the main identified genetic causes of autism spectrum disorder. This proposal investigates neuronal development in a mouse model of FXS by imaging dendritic spines, critical components of the connection between neurons, in order to determine if model interventions are capable of restoring function to this system after birth. Ultimately, we are asking how abnormalities in spine morphology, found in the majority of causes of mental retardation, relate to behavioral function and cognition.