Several genetically defined developmental disorders that manifest as autism and intellectual disability, such as fragile X (FX) and tuberous sclerosis complex (TSC), have in common a disruption of activity-regulated protein synthesis at synapses. Understanding how neural activity regulates synaptic protein synthesis is crucial for identifying new therapuetic approaches for these diseases. One key mechanism employs metabotropic glutamate receptor 5 (mGluR5) but it remains to be established how this receptor couples to the mRNA translation machinery. Here we test the hypothesis that a crucial link between mGluR5 and protein synthesis is provided by -arrestin.
Our specific aims are to characterize the effect of ss-arrestin genetic reduction on (1) mGluR5 signaling and protein synthesis in the hippocampus using biochemical methods, (2) hippocampal synaptic function and protein synthesis-dependent plasticity using electrophysiological methods, and (3) on fragile X behavioral and electrophysiological phenotypes expressed in the Fmr1 knockout mouse. If our hypothesis is correct, we expect to observe an amelioration of fragile X phenotypes by reducing -arrestin, validating the mGluR5--arrestin protein complex as a novel therapeutic target.

Public Health Relevance

Fragile X syndrome, tuberous sclerosis complex, and several other genetic disorders with increased risk of autism and intellectual disability are caused by mutations of genes involved in the regulation of protein synthesis at synaptic connections between neurons. Understanding how synaptic protein synthesis is regulated promises to reveal new molecular targets for correction of the core pathophysiology in these diseases.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS087225-01
Application #
8677025
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mamounas, Laura
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142