|Pharmacologic Treatment of Social Deficits in a Mouse Model for Fragile X Syndrome: Do Gene-Gene Interactions Play a Role?
by Jean Lauder, 2/1/2005
The goal of this project is to investigate drug therapies for treating autism-like behaviors (social deficits) in Fragile X Syndrome (FX). These studies take advantage of evidence that the FX null mutation (knockout of the gene encoding the Fragile X mental retardation protein) has greater effects on both social behavior and gene expression in mice on one genetic background
(FVB/129) compared to another (C57BL/6).
This raises two important questions:
1) does genetic background play a role in development of autistic behavior in FX, and
2) does genetic background impact the success of drug therapies in treating abnormal
social behavior in FX?
The experiments will determine the effectiveness of acute or chronic
drug treatments on social behavior in FVB/129 and C57Bl/6 FX mutant mice compared to their wildtype (normal) counterparts.
Three drugs will be tested which affect different neurotransmitter
systems (brain chemicals). These include Abilify and Risperidone, which block both dopamine and
serotonin receptors, MPEP, which blocks glutamate (mGluR5) receptors, and lithium, a non-specific antipsychotic that affects multiple neurotransmitter systems. Young adult male mutant and wildtype mice will be treated acutely (once) with different doses of each drug, or chronically (for several days) with the most effective drug(s) and dose(s) found in the acute study.
Drug effects on social behavior
will be tested using an automated system that measures the length of time a test mouse spends visiting
a strange mouse in an adjacent chamber, compared to an empty chamber. A test for social novelty is then conducted by replacing the strange mouse with a new stranger to see if the test mouse is interested in
visiting the new mouse.
The goal is to determine which drugs are most effective in making the mutant mice more interested in social contact. Mechanisms contributing to effective drug therapies will be investigated using cellular and molecular methods to profile drug effects on brain gene expression.
Understanding these mechanisms will aid in future drug development, and could enhance our understanding of functional brain abnormalities that contribute to autistic behaviors in Fragile X.