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Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome

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Abstract

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.

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Acknowledgements

This research was supported by the Baylor Fragile X Center, the Baylor EKS IDDRC (NICHD), and the FRAXA Research Foundation. A.M.T. received partial support from NIGMS training grant T32 GM08307. We greatly appreciate the valuable input and advice provided by Dr. Corinne Spencer, Surabi Veeraragavan, Shannon Hamilton, and Randi-Michelle Cowin during the course of the project.

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  1. Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Alexia M. Thomas & Richard Paylor

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Nghiem Bui, Jennifer R. Perkins, Lisa A. Yuva-Paylor & Richard Paylor

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  1. Alexia M. Thomas
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Correspondence to Richard Paylor.

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Thomas, A.M., Bui, N., Perkins, J.R. et al. Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome. Psychopharmacology 219, 47–58 (2012). https://doi.org/10.1007/s00213-011-2375-4

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