Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures
Abstract
Mice lacking the gene encoding fragile X mental retardation protein (FMR1) are susceptible to audiogenic seizures, and antagonists of the group I metabotropic glutamate receptors (mGluRs) have been shown to block seizures in FMR1 knockout mice. We investigated whether the G-protein-inhibitory activity of the regulator of G-protein signaling protein, RGS4, could also alter the susceptibility to audiogenic seizures in FMR1 mice. We were surprised to find that male FMR1/RGS4 double-knockout mice showed reduced susceptibility to audiogenic seizures compared with age-matched FMR1 mice. These data raised the intriguing possibility that loss of RGS4 increased signaling through another G-protein pathway that reduces seizure susceptibility in FMR1 mice. Indeed, administration of the GABA(B) receptor agonist baclofen to FMR1 mice inhibited seizures, whereas the GABA(B) receptor antagonist (3-aminopropyl)(cyclohexylmethyl)phosphinic acid (CGP 46381) increased seizure incidence in double-knockout mice but not in wild-type mice. Finally, audiogenic seizures could be induced in wild-type mice by coadministering CGP 46381 and the mGluR5-positive allosteric modulator 3-cyano-N-(1,2 diphenyl-1H-pyrazol-5-yl) benzamide. These data show for the first time that GABA(B) receptor-mediated signaling antagonizes the seizure-promoting effects of the mGluRs in FMR1 knockout mice and point to the potential therapeutic benefit of GABA(B) agonists for the treatment of fragile X syndrome.
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Baclofen reduced the susceptibility of Fmr1 knockout mice to audiogenic seizures.
“Baclofen, a GABA B -R agonist, reduced the susceptibility of Fmr1 KO mice to audiogenic seizures (117).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [117]
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Self-citation
- Authors
- Pacey, L. K. K., Heximer, S. P., & Hampson, D. R.
- Affiliations
- University of Toronto (CA)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 76
- Issue
- 1
- Pages
- 18-24
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2157348568
- Cited by
- 133
- References
- 44
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 12 · 2016: 9 · 2015: 7 · 2014: 15 · 2013: 12 · 2012: 16
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- GABAB receptors, audiogenic seizures, fragile X syndrome, Fmr1 knockout mice, RGS4, group I metabotropic glutamate receptors, mGluR5, baclofen, seizure susceptibility, G protein signaling, FMRP
- MeSH terms
- Animals, Baclofen, Disease Susceptibility, Female, Male, Mice, Inbred C57BL, Phosphinic Acids, Seizures, Signal Transduction, Receptors, GABA-B, Receptors, Metabotropic Glutamate, Mice, Knockout, RGS Proteins, Mice, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein, Receptor, Metabotropic Glutamate 5
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