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

• Published in: Psychopharmacologia Vol. 219; no. 1; pp. 47 - 58
• Main Authors: Thomas, Alexia M., Bui, Nghiem, Perkins, Jennifer R., Yuva-Paylor, Lisa A., Paylor, Richard
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-01-2012; Springer; Springer Nature B.V
• Subjects: Acoustic Stimulation - methods; Amino acids; Animal behavior; Animal models; Animals; Antagonists; Auditory stimuli; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Data processing; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; fragile X mental retardation protein; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - psychology; Glutamate; Glutamic acid receptors (metabotropic); Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Miscellaneous; Motor skill learning; Neurosciences; Original Investigation; Pathogenesis; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Psychiatry; Quinolines - pharmacology; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - physiology; Reflex, Startle - drug effects; Reflex, Startle - physiology; Rodents; Seizures; Seizures (Medicine); Behavior; Mouse; Fragile X; Metabotropic glutamate receptor; Fmr1; Fmrl; Chromosome fragility; Animal model; Group I mglu glutamate receptor; Rodentia; Glutamate receptor; Vertebrata; Mammalia; Metabotropic receptor; Animal; Antagonist; Fragile X syndrome
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-011-2375-4

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.