Abstracts

Rationale: Mice lacking voltage-gated Kv1.1 channels due to deletion of the Kcna1 gene are an extensively utilized genetic model of human epilepsy and sudden unexpected death in epilepsy (SUDEP) due to their frequent seizures and genotypic-phenotypic similarity to the human condition. Ictal behaviors, electrophysiological recordings, and gene expression studies suggest limbic circuits are critical for epilepsy in Kcna1-null (KO) mice, but the exact brain networks recruited by seizures remain unknown.Methods: Kcna1-null mice were video monitored in their home cages to identify behavioral seizures. Fos protein expression patterns were then used to map limbic brain regions with increased neuronal activity at baseline and during spontaneous seizures in Kcna1-null mice by comparing seizing (n=6) and non-seizing KOs (n=7) and wildtype (WT) controls (n=9). Seizing mice were defined as those exhibiting obvious behavioral seizures during the 4 h immediately preceding tissue harvesting.Results: Basal Fos levels were unchanged in non-seizing KO mice compared to WT for all brain regions examined except the dentate gyrus granule cell layer which exhibited a significant 75% decrease in Fos-positive cells (P<0.01). Following seizures, Kcna1-null brains exhibited significant 4-fold increases in Fos labeling in the basolateral amygdala (P<0.01) and the dentate hilus region (P<0.05), but not in other principal cell layers of the hippocampal formation.Conclusions: The selective Fos activation in the amygdala following seizures suggests that extrahippocampal limbic circuits may be critically involved with seizure generation or spread in Kcna1-null mice. These findings are significant because provide the first map of brain regions recruited by spontaneous seizures in Kcna1-null mice, a commonly used genetic model of epilepsy and SUDEP. This work was supported by a grant from the National Institutes of Health (R00HL107641).