Molecular Imaging of Synaptic Signaling in Fragile X Neurons

Scott H. Soderling, Ph.D.

Duke University, Durham, NC

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

June 2008, for 3 years

Funding Amount:


Lay Summary

Exploring the Genetic Basis of Fragile X Syndrome at the Molecular Level

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.


Molecular Imaging of Synaptic Signaling in Fragile X Neurons

Mental retardation is the leading cause of developmental disability in children and affects between 2-3% of the population in the United States.  Much progress has been made in identifying genes that when mutated are associated with MR in humans. From these studies, it is increasingly apparent that mutations in genes encoding proteins that regulate signaling to the actin cytoskeleton in dendritic spines are associated with MR.

The leading cause of inherited mental retardation is Fragile X syndrome (FXS), which is caused by mutations in the FMR1 gene and loss of functional FMRP (Fragile X Mental Retardation Protein). It is well accepted that FMRP normally functions in dendritic spines to limit translation and Long-Term Depression (LTD) downstream of the metabotropic receptor mGluR5. Thus, FXS is believed to be a disease of excess translation that ultimately leads to elevated LTD and mental retardation.  There is a critical unmet need to understand the molecular mechanisms of how loss of FMRP alters synaptic plasticity and leads to FXS. Lack of such knowledge is an important problem because it hinders our ability to imagine how FXS may be corrected.  The overall objective of this proposal is to use high resolution imaging techniques and unique mouse genetic models to address how mutations in FMR1 lead to abnormalities in actin-rich spines and synaptic plasticity.

Investigator Biographies

Scott H. Soderling, Ph.D.

Dr. Soderling was trained in the Department of Pharmacology at the University of Washington (Ph.D.) and the Vollum Institute at OHSU (Postdoctoral work).  During his postdoctoral work Dr. Soderling discovered a cytoskeletal signaling complex that regulates synapse formation and function in central nervous system.  Mutations in this complex may be associated with forms of human mental retardation.

Following on this work, his laboratory is interested in two broad questions. 1) How is Rho-family GTPase signaling to the actin cytoskeleton in neurons regulated by multi-protein complexes? 2) How does the organization of these signaling pathways translate to the regulation of normal neuronal function and how does loss of these pathways lead to illnesses such as mental retardation?  To answer these questions, his laboratory utilizes a combination of biochemistry, molecular biology, cellular imaging, and mouse genetics.