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Updated: Jun 1, 2026
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome
Alexia M Thomas1, Nghiem Bui, Jennifer R Perkins
1Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Rationale:
Studies in the Fmr1 knockout (KO) mouse, a model of fragile X syndrome (FXS), suggest that excessive signaling through group I metabotropic glutamate receptors (mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role in the pathogenesis of FXS. Currently, no studies have assessed the effect of mGluR1 modulation on Fmr1 KO behavior, and there has not been an extensive behavioral analysis of mGluR5 manipulation in Fmr1 KO mice.
Objectives:
The goals for this study were to determine if pharmacologic blockade of mGluR1 may affect Fmr1 KO behavior as well as to expand on the current literature regarding pharmacologic blockade of mGluR5 on Fmr1 KO behavior.
Methods:
Reduction of mGluR1 or mGluR5 activity was evaluated on a variety of behavioral assays in wild-type (WT) and Fmr1 KO mice through the use of antagonists: JNJ16259685 (JNJ, mGluR1 antagonist) and MPEP (mGluR5 antagonist).
Results:
JNJ and MPEP decreased marble burying in both WT and Fmr1 KO mice without reductions in activity. Neither JNJ nor MPEP affected the prepulse inhibition in either WT or Fmr1 KO mice. JNJ did not affect Fmr1 KO motor coordination but did impair WT performance. MPEP improved a measure of motor learning in Fmr1 KO but not WT mice. While both JNJ and MPEP decreased the audiogenic seizures in the Fmr1 KO, MPEP completely abolished the manifestation of seizures.
Conclusion:
These data illustrate that, while the manipulation of either mGluR1 or mGluR5 can affect select behaviors in the Fmr1 KO, we observe greater effects upon mGluR5 reduction.
Insights
Pharmacologic blockade of metabotropic glutamate receptors (mGluRs) in Fmr1 KO mice showed that mGluR5 reduction had greater effects on behavior than mGluR1 modulation. These findings advance understanding of fragile X syndrome (FXS) pathogenesis.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Fragile X syndrome (FXS) pathogenesis may involve excessive signaling via group I metabotropic glutamate receptors (mGluRs), specifically mGluR1 and mGluR5.
- Previous research has not fully explored the impact of mGluR1 modulation or extensively analyzed mGluR5 manipulation in Fmr1 knockout (KO) mouse models of FXS.
Purpose of the Study:
- To investigate the behavioral effects of pharmacologically blocking mGluR1 in Fmr1 KO mice.
- To expand the understanding of mGluR5 blockade's impact on Fmr1 KO mouse behavior.
Main Methods:
- Wild-type (WT) and Fmr1 KO mice were treated with JNJ16259685 (JNJ, an mGluR1 antagonist) and MPEP (an mGluR5 antagonist).
- Behavioral assays included marble burying, prepulse inhibition, motor coordination, motor learning, and audiogenic seizures.
Main Results:
- Both JNJ and MPEP reduced marble burying in WT and Fmr1 KO mice without affecting general activity.
- Neither antagonist altered prepulse inhibition. JNJ impaired WT motor coordination, while MPEP improved motor learning in Fmr1 KO mice.
- Both antagonists decreased audiogenic seizures in Fmr1 KO mice, with MPEP completely abolishing them.
Conclusions:
- Modulation of either mGluR1 or mGluR5 impacts specific behaviors in Fmr1 KO mice.
- Reduction of mGluR5 activity demonstrated more significant behavioral effects compared to mGluR1 reduction in the Fmr1 KO model.
