Increased sensitivity to agonist-induced seizures, straub tail, and hippocampal theta rhythm in knock-in mice carrying hypersensitive alpha 4 nicotinic receptors.
We studied a strain of exon replacement mice ("L9'S knock-in") whose alpha4 nicotinic receptor subunits have a leucine to serine mutation in the M2 region, 9' position (Labarca et al., 2001); this mutation renders alpha4-containing receptors hypersensitive to agonists. Nicotine induced seizures at concentrations (1 mg/kg) approximately eight times lower in L9'S than in wild-type (WT) littermates. At these concentrations, L9'S but not WT showed increases in EEG amplitude and theta rhythm. L9'S mice also showed higher seizure sensitivity to the nicotinic agonist epibatidine, but not to the GABA(A) receptor blocker and proconvulsant bicuculline. Dorsiflexion of the tail (Straub tail) was the most sensitive nicotine effect found in L9'S mice (0.1 mg/kg). The L9'S mice were hypersensitive to galanthamine- and tacrine-induced seizures and Straub tails. There were no apparent neuroanatomical differences between L9'S and WT mice in several brain regions. [(125)I]Epibatidine binding to brain membranes showed that the mutant allele was expressed at approximately 25% of WT levels, presumably because of the presence of a neomycin selection cassette in a nearby intron. (86)Rb efflux experiments on brain synaptosomes showed an increased fraction of function at low agonist concentrations in L9'S mice. These data support the possible involvement of gain-of-function alpha4 receptors in autosomal dominant nocturnal frontal-lobe epilepsy.
Fonck
Carlos
C
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Nashmi
Raad
R
Deshpande
Purnima
P
Damaj
M Imad
MI
Marks
Michael J
MJ
Riedel
Anett
A
Schwarz
Johannes
J
Collins
Allan C
AC
Labarca
Cesar
C
Lester
Henry A
HA
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000503:physiopathology; D004569:Electroencephalography; D005260:Female; D018628:Gene Dosage; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009538:Nicotine; D018722:Nicotinic Agonists / Q000633:toxicity*; D010641:Phenotype; D011978:Receptors, Nicotinic / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D013623:Tail; D013826:Theta Rhythm
D009538:Nicotine; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic