Investigators will combine molecular imaging with genetics research to determine how a specific gene mutation leads to abnormal brain cell communication in a mouse model of Fragile X syndrome, the most common inherited form of mental retardation.
Fragile X syndrome primarily affects boys. They inherit mutated forms of the FMR1 gene, which ultimately results in development of abnormal neural networks and subsequent learning disabilities. The FMR1 gene is known to produce a protein called “FMRP.” Evidence suggests that this FMRP protein ordinarily regulates synthesis of proteins that regulate actin, which is integrally involved in brain cell-to-cell communication. Actin protein resides in the dendritic spines, which are tiny bulb-like structures on dendrites that extend from the brain cell body and receive messages from neighboring brain cells.
The researchers hypothesize that mutations resulting in the loss of the FMRP protein lead to the deregulation of actin, which then alters the abilities of dendritic spines to receive and interpret neural messages. The resulting abnormal neuronal network connections then lead to Fragile X syndrome. Specifically, they hypothesize, loss of FMRP protein results in inappropriate translation of brain actin signaling pathways that result in an inability of neurons to interpret information from the neurotransmitter glutamate. They will test this hypothesis using a type of molecular imaging called “fluorescence recovery after photobleaching” (FRAP), in a mouse model of Fragile X syndrome. Using cellular imaging of individual dendritic spines, they will quantify the extent of actin remodeling and the changes this produces in the way electrochemical signals are received and stored by dendritic spines.
Significance: The study may provide a consolidated picture of how the loss of the FMRP protein relates to specific signaling pathway abnormalities in Fragile X syndrome, potentially leading to new therapeutic approaches.