Fragile X Center Project 2: Gp1 mGluRs as Candidate Modifiers of Fmr1KO Phenotypes
Fragile X syndrome is the most common form of inherited mental retardation. Fragile X syndrome is caused by the expansion of an unstable CGG trinucleotide repeat in exon 1 of the FMR1 gene. Individuals with this disorder have several physical abnormalities including atypical facial features, macroorchidism, and mental retardation. In addition, individuals with fragile X have several behavioral abnormalities including hyperactivity, hyperarousal, and increased anxiety especially in social situations. Though mental retardation and several behavioral abnormalities are presented in individuals with fragile X, there is significant variability in the expression of these abnormalities. We speculate that a portion of this variation is due to the presence/absence of other modifier genes. To better understand the contribution of genetic background to behavioral variability associated with fragile X, we have recently completed a study that demonstrates genetic background can indeed dramatically impact the behavioral responses of Fmr1 KO mice. The primary overall goal of the current project is to test the hypothesis that group1 (Gp1) mGluR receptors (mGluR5 and/or mGluR1) are candidate modifiers of Fmr1 KO mice. We propose to study the role of a candidate modifier that may contribute the regulation of behavioral, electrophysiological, and neuroanatomical phenotypes in the Fmr1 KO mouse model of FXS. We have developed the following aims for this project:
- Determine if reductions in mGluR5 or mGluR1 function using compound mutant mice, and pharmacological interventions modulates behavioral responses in Fmr1 KO mice.
- Determine if reductions in mGluR5 or mGluR1 using compound mutant mice modulates LTD and dendritc spine morphology in Fmr1 KO mice.
- Determine if reductions in mGluR5 or mGluR1 using compound mutant mice modulates increased protein expression in Fmr1 KO mice.
At the completion of this project we will have a better understanding of the role of Gp1 mGluRs as modifiers of FMRP, and evaluated the role of potential therapeutic interventions at mGluRs in multiple modalities of CNS function that are altered in FXS.
Relevance of the project to IDDRC mission:
Fragile X is the most common form of inherited mental retardation. Understanding of the role of Gp1 mGluRs as modifiers of FMRP, and evaluating the role of potential therapeutic interventions at mGluRs could translate to treatments of FXS.