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Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP
Abstract
Fragile X Syndrome is the most common form of inherited mental retardation worldwide. A Fragile X mouse model, fmr1(tm1Cgr), with a disruption in the X-linked Fmr1 gene, has three substantial deficits observed in several strains: (1) sensitivity to audiogenic seizures (AGS), (2) tendency to spend significantly more time in the center of an open field, and (3) enlarged testes. Alterations in metabotropic glutamate receptor group I signaling were previously identified in the fmr1(tm1Cgr) mouse. In this study, we examined the effect of MPEP, an antagonist of the group I metabotropic glutamate receptor mGluR5, on audiogenic seizures and open field activity of fmr1(tm1Cgr) mice. Genetic analysis revealed synergistic reactions between fmr1(tm1Cgr) and inbred AGS alleles. In addition, AGS sensitivity due to the fmr1(tm1Cgr) allele was restricted during development. Examination of phenotypes combining mGluR5 inhibition and Fmr1 mutation indicated that absence of FMRP may affect mGluR5 signaling through indirect as well as direct pathways. All strains of fmr1(tm1Cgr) mice tested (FVB/NJ, C57BL/6J, and an F1 hybrid of the two) had a more excitable AGS pathway than wild-type, and consequently required more MPEP to achieve seizure suppression. At high doses of mGluR5 antagonists, a Fragile X specific tolerance (loss of drug activity) was observed. The tolerance effect could be overcome by a further increase in drug dose. In open field tests, MPEP reduced fmr1(tm1Cgr) center field behavio…
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“have demonstrated that dampening mGluR5 signalling rescues protein synthesis and many of the classic outcome measures (TABLE 1) used in the mouse and fly models30–35.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [35]
Experimental — accuracy not yet measuredIn the citing paper
“Preclinical studies have primarily focused on mGluR5 signaling as potential targets for treatment in adult mice 99,110-113 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [113]
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“Treatment of Fmr1 KO mice with the mGluR antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (Figure 3B) resulted in suppression of the audiogenic seizure phenotype (106) and rescue of dendritic spine morphology in the Fmr1 KO mouse (107).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [106]
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Metadata
- Authors
- Yan, Q. J., Rammal, M., Tranfaglia, M., & Bauchwitz, R. P.
- Affiliations
- Columbia University (US)
- Fraxa Research Foundation (US)
- Corresponding author
- Bauchwitz, R.P.
- ORCID
- Bauchwitz, R.P.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 49
- Issue
- 7
- Pages
- 1053-1066
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2094993063
- Cited by
- 521
- References
- 60
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 12 · 2021: 16 · 2020: 13 · 2019: 10 · 2018: 12 · 2017: 28 · 2016: 26 · 2015: 26 · 2014: 30 · 2013: 45 · 2012: 47
- FWCI
- 13.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- CogPrints (University of Southampton) (submittedVersion)
- Funders
- FRAXA Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Keywords
- fragile X syndrome, FMR1 gene, mGluR5, MPEP, audiogenic seizures, testicular enlargement, FMRP, drug tolerance, seizure susceptibility, mouse model
- MeSH terms
- Aging, Alleles, Animals, Drug Synergism, Exploratory Behavior, Female, Fragile X Syndrome, Genotype, Male, Mice, Inbred C57BL, Phenotype, Pyridines, Receptors, Metabotropic Glutamate, Epilepsy, Reflex, Mice, Fragile X Messenger Ribonucleoprotein 1, Receptor, Metabotropic Glutamate 5
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