Abstracts

RATIONALE: 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. The objective of the present study was to characterize the effects of the M current-selective antagonist linopirdine (LPD) on electroconvulsive seizure thresholds (ECT) in mice heterozygous for a spontaneous deletion mutation ([italic]Szt1[/italic], seizure threshold 1), which deletes the C-terminal half of KCNQ2, as well as the [italic]Chrna4[/italic] locus and at least one other known gene on mouse Chr 2, [italic]Arfgap1[/italic] (ADP-ribosylation factor 1 GTPase activating). These mice, by virtue of lethal lung defects in the homozygotes and generally normal appearance in the heterozygotes, appear much like the published [italic]Kcnq2[/italic] null mutants of Watanabe and colleagues (2001).
METHODS: Stimulus currents of differing intensities and frequencies were delivered through transcorneal electrodes to evoke three types of seizures: partial psychomotor, minimal clonic, and maximal tonic hindlimb extension (THE). Convulsive current (CC) curves for each seizure type were constructed using BALB/cByJ and BALB.B6-[italic]Szt1[/italic]/+ mice to elicit baseline differences in seizure threshold between the strains. At the calculated CC[sub]25[/sub] values, both strains were then injected with LPD (10 mg/kg) or 0.5% methylcellulose (control) and tested for each seizure type to determine the effects of LPD on seizure thresholds.
RESULTS: Results obtained from this study demonstrate that the seizure threshold of BALB.B6-[italic]Szt1[/italic]/+ mice is significantly lowered relative to BALB/cByJ mice in all seizure types tested. LPD treatment significantly lowers the seizure thresholds of both mouse strains in all seizure types tested. LPD does not appear to preferentially affect one strain more than the other in partial or maximal seizure testing. Interestingly, however, when tested for minimal clonic seizures, 9 of 9 LPD-treated BALB.B6-[italic]Szt1[/italic]/+ mice had seizures, with 6 of these 9 mice progressing to maximal THE seizures.
CONCLUSIONS: Our results show that the spontaneous [italic]Szt1[/italic] mutation in the [italic]Kcnq2[/italic] gene decreases partial psychomotor, minimal clonic, and maximal THE seizure thresholds as determined by ECT testing. In addition, the M current antagonist LPD further decreases the seizure thresholds of both strains, indicating that both normal- and reduced-function M-type K⁺ channels are sensitive to M current antagonists. The magnitude of shift induce by LPD in the minimal clonic seizure test in the BALB.B6-[italic]Szt1[/italic]/+ strain suggests that the [italic]Szt1[/italic] mutation confers increased sensitivity to the effects of LPD.
[Supported by: NIH: 5-RO1-NS-40246 (WNF, HSW)]