Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures.
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.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Laura K K
LK
Pacey
Scott P
SP
Heximer
David R
DR
Hampson
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004198:Disease Susceptibility; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010721:Phosphinic Acids / Q000494:pharmacology; D020710:RGS Proteins / Q000235:genetics / Q000502:physiology*; D064529:Receptor, Metabotropic Glutamate 5; D018080:Receptors, GABA-B / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis / Q000502:physiology; D012640:Seizures / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*
D001418:Baclofen; D051860:Fragile X Messenger Ribonucleoprotein 1; D010721:Phosphinic Acids; D020710:RGS Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C578936:Grm5 protein, mouse; C086109:3-aminopropyl-cyclohexylmethylphosphinic acid; C098799:RGS4 protein