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Molecular Pharmacology

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Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures

Laura K. K. Pacey, Scott P. Heximer and David R. Hampson
Molecular Pharmacology July 2009, 76 (1) 18-24; DOI: https://doi.org/10.1124/mol.109.056127
Laura K. K. Pacey
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Scott P. Heximer
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David R. Hampson
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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 GABAB receptor agonist baclofen to FMR1 mice inhibited seizures, whereas the GABAB 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 GABAB receptor-mediated signaling antagonizes the seizure-promoting effects of the mGluRs in FMR1 knockout mice and point to the potential therapeutic benefit of GABAB agonists for the treatment of fragile X syndrome.

Footnotes

  • This work was supported by the Fragile X Research Foundation of Canada and the Canadian Institutes for Health Research [Grant MOP-81179].

  • ABBREVIATIONS: FMRP, fragile X mental retardation protein; GPCR, G-protein-coupled receptors; KIR, inward-rectifying potassium; mGluR, metabotropic glutamate receptor; CGP 46381, (3-aminopropyl)(cyclohexylmethyl)phosphinic acid; RGS, regulator of G-protein signaling; CDPPB, 3-cyano-N-(1,2 diphenyl-1H-pyrazol-5-yl) benzamide; PCR, polymerase chain reaction; bp, base pair(s); RT-PCR, reverse-transcription polymerase chain reaction; KO, knockout.

    • Accepted April 6, 2009.
    • Received March 10, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (1)
Molecular Pharmacology
Vol. 76, Issue 1
1 Jul 2009
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Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures

Laura K. K. Pacey, Scott P. Heximer and David R. Hampson
Molecular Pharmacology July 1, 2009, 76 (1) 18-24; DOI: https://doi.org/10.1124/mol.109.056127

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Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures

Laura K. K. Pacey, Scott P. Heximer and David R. Hampson
Molecular Pharmacology July 1, 2009, 76 (1) 18-24; DOI: https://doi.org/10.1124/mol.109.056127
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