Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel.
OBJECTIVE
Mutations in the genes that encode subunits of the M-type K+ channel (KCNQ2/KCNQ3) and nicotinic acetylcholine receptor (CHRNA4) cause epilepsy in humans. The purpose of this study was to examine the effects of the Szt1 mutation, which not only deletes most of the C-terminus of mouse Kcnq2, but also renders the Chnra4 and Arfgap-1 genes hemizygous, on seizure susceptibility and sensitivity to drugs that target the M-type K+ channel.


METHODS
The proconvulsant effects of the M-channel blocker linopirdine (LPD) and anticonvulsant effects of the M-channel enhancer retigabine (RGB) were assessed by electroconvulsive threshold (ECT) testing in C57BL/6J-Szt1/+ (Szt1) and littermate control C57BL/6J+/+ (B6) mice. The effects of the Szt1 mutation on minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures were evaluated by varying stimulation intensity and frequency.


RESULTS
Szt1 mouse seizure thresholds were significantly reduced relative to B6 littermates in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Mice were injected with LPD and RGB and subjected to ECT testing. In the minimal clonic seizure model, Szt1 mice were significantly more sensitive to LPD than were B6 mice [median effective dose (ED50) = 3.4 +/- 1.1 mg/kg and 7.6 +/- 1.0 mg/kg, respectively]; in the partial psychomotor seizure model, Szt1 mice were significantly less sensitive to RGB than were B6 mice (ED50 = 11.6 +/- 1.4 mg/kg and 3.4 +/- 1.3 mg/kg, respectively).


CONCLUSIONS
These results suggest that the Szt1 mutation alters baseline seizure susceptibility and pharmacosensitivity in a naturally occurring mouse model.
Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
James F
JF
Otto
Yan
Y
Yang
Wayne N
WN
Frankel
Karen S
KS
Wilcox
H Steve
HS
White
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004597:Electroshock; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D007211:Indoles / Q000494:pharmacology; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics*; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics; D012640:Seizures / Q000235:genetics* / Q000517:prevention & control; D017384:Sequence Deletion / Q000235:genetics
D000927:Anticonvulsants; D002219:Carbamates; D007211:Indoles; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C114401:Kcnq2 protein, mouse; C496917:Kcnq3 protein, mouse; D009419:Nerve Tissue Proteins; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D011978:Receptors, Nicotinic; C101866:ezogabine; C061017:linopirdine