Abstracts

Benign familial neonatal convulsions (BFNC) is caused by reduction-of-function mutations in the genes that encode the KCNQ2 or KCNQ3 subunits of the M-type K⁺ channel, which underlies the M current. We utilized the B6-[italic]Szt1[/italic]/+ ([italic]Szt1[/italic]) mouse, which contains a spontaneous C-terminal deletion in the KCNQ2 subunit (Yang et al., 2003; Hum Mol Genet, 12: 975-984), as a model of genetically altered M current function. Using [italic]Szt1[/italic] and wild-type B6 mice, we 1) examined differences in seizure threshold and 2) evaluated the ability of drugs that act at the M-channel to modify seizure susceptibility.
Transcorneal stimulation was used to evoke three types of seizures: partial psychomotor, minimal clonic, and minimal tonic hindlimb extension (THE). Convulsive current (CC) curves for each seizure type were constructed using B6 and [italic]Szt1[/italic] mice. At the calculated CC[sub]10[/sub], CC[sub]90[/sub], and CC[sub]50[/sub] values for each strain, mice were injected with either linopirdine (LPD, an M-channel blocker), retigabine (RGB, an enhancer), or LPD + RGB, respectively, and tested for seizure incidence. All drug injections were i.p., 10 mg/kg, and methyl cellulose (MeCell) was used as a vehicle control. RGB dose/response curves were also constructed in the partial psychomotor model.
In all seizure types tested, we observed significant decreases in the thresholds of [italic]Szt1[/italic] mice relative to B6 mice. In both strains, we also observed significant gender-dependent differences in seizure threshold. The RGB dose/response data show that in the psychomotor model, RGB is less potent in [italic]Szt1[/italic] mice than in B6 mice. Moreover, several strain-dependent differences in seizure incidence arose in response to treatment with LPD and RGB (see table).[table1]
Our data suggest that mice with presumably compromised M current function have reduced seizure thresholds, and that this increase in net neuroexcitability can also confer increased sensitivity to M-channel modulating drugs. Our results also indicate that these altered drug senstivities are dependent on the seizure type elicited. Finally, these data shed light on the implications of genetically altered M-channels and their role in altered pharmacoresponsiveness and seizure susceptibility.
[Supported by: NIH 5-RO1-NS-40246 (WNF, HSW), Primary Children[apos]s Medical Center Foundation 51001142 (KSW)]