Abstracts

A dominant, gain-of-function mutation in the voltage-gated sodium channel [italic]Scn2a [/italic]results in epilepsy in [italic]Q54[/italic] transgenic mice. The mice have adult-onset, progressive epilepsy beginning with short duration partial seizures that originate in the hippocampus (Kearney et al, 2001, Neurosci, 102:307). The hippocampus shows pathologic features of mesial temporal lobe epilepsy including mossy fiber sprouting and extensive loss of CA1, CA3 and hilar neurons. M current (I[sub]KM[/sub]) is thought to play a critical role in controlling the excitability and limiting repetitive firing of hippocampal neurons (Cooper et al, 2001, J Neurosci 21:9529).[italic] Szt1[/italic] mice have a spontaneous C-terminal deletion of the voltage-gated potassium channel [italic]Kcnq2[/italic] which underlies M current in neurons. Heterozygous [italic]Szt1/+[/italic] mice have lowered threshold to seizures induced by trans-corneal stimulation or PTZ, although they do not have spontaneous seizures. [italic]Kcnq2[/italic] transcript is reduced in [italic]Szt1/+[/italic] brain and lowered seizure threshold is thought to result from reduction of M current (Yang et al, 2003, Human Mol Genet 12:975). We examined the effect of reduced M-current function on the epilepsy phenotype of [italic]Q54[/italic] mice by analysis of [italic]Q54[/italic]-[italic]Szt1[/italic] double mutants. C57BL/6J.[italic]Q54[/italic] mice were crossed with C57BL/6J.[italic]Szt1[/italic]/+ mice to generate [italic]Q54-Szt1[/italic] double mutants. Mice were genotyped at 12 days of age and monitored for visible seizures and survival. Single mutant [italic]Q54[/italic] and [italic]Szt1[/italic]/+ mice do not exhibit spontaneous seizures or lethality during the first three weeks of life. In contrast, [italic]Q54[/italic]-[italic]Szt1 [/italic]double mutant mice have a severe, early-onset epilepsy with prolonged generalized tonic-clonic seizures beginning in the 3^rd week of life. Most double mutants do not survive beyond 3 weeks of age. The short duration, partial seizures in [italic]Q54[/italic] mice begin in adulthood and result from an [italic]Scn2a [/italic]mutation with increased persistent sodium current. The phenotype of double mutant [italic]Q54[/italic]-[italic]Szt1[/italic] mice is much more severe, with very early onset of prolonged generalized seizures. These results suggest that M current is important for preventing seizure initiation and spreading in Q54 mice. The genetic interaction between [italic]Scn2a[/italic] and [italic]Kcnq2[/italic] suggests that interaction between mild alleles of known monogenic epilepsy genes may contribute to the complex inheritance of human epilepsy. (Supported by NIH R21 NS046315 (JAK))