Proconvulsant-induced seizures in alpha(4) nicotinic acetylcholine receptor subunit knockout mice.
The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby these mutations produce seizures is unknown. Three mutations of the alpha(4) subunit of the neuronal nicotinic acetylcholine receptor (nAChR) have been identified in autosomal dominant nocturnal frontal lobe epilepsy. In vitro studies of two mutations suggest an alteration of receptor function resulting in decreased ion channel current flow. We investigated the response of alpha(4) nAChR subunit knockout mice to the gamma-aminobutyric acid (GABA) receptor antagonists; pentylenetetrazole (PTZ) and bicuculline (BIC), the glutamate receptor agonist kainic acid (KA), the glycine receptor antagonist strychnine and the K(+) channel blocker 4-aminopyridine (4-AP). Mutant (Mt) mice had a greater sensitivity to PTZ and BIC, with an increase in major motor seizures and seizure-related deaths. Furthermore, Mt mice were more sensitive to KA and strychnine, but the effects were much smaller compared to those seen with the GABA receptor antagonists. Paradoxically, Mt mice appeared to be relatively protected from 4-AP-induced major motor seizures and death. The results show that a functional deletion of the alpha(4) nAChR subunit in vivo is associated with a major increase in sensitivity to GABA receptor blockers.
Wong
John Y F
JY
Neurosciences Group, Monash University Department of Medicine, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Ross
Shelley A
SA
McColl
Craig
C
Massalas
Jim S
JS
Powney
Emma
E
Finkelstein
David I
DI
Clark
Malcolm
M
Horne
Malcolm K
MK
Berkovic
Samuel F
SF
Drago
John
J
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D005838:Genotype; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010433:Pentylenetetrazole / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D013331:Strychnine / Q000494:pharmacology
D015761:4-Aminopyridine; D001640:Bicuculline; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D007608:Kainic Acid; D010433:Pentylenetetrazole; D026902:Potassium Channel Blockers; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D013331:Strychnine