Abstracts

RATIONALE: We investigated the effects of a ketogenic diet (KD) on the survivability of severe, spontaneously epileptic mice (i.e., Kv1.1 null [-/-] mutants), and examined the hippocampi of these mice for evidence of altered synaptic reorganization in the dentate gyrus. METHODS: Kv1.1 -/- mice were fed ad libitum with either standard chow (n=38) or a ketogenic diet (Ziegler Bros.; n=10) beginning at P22-25. Blood ?-hydroxybutyrate (BHB) levels were determined with the Keto-Site reflectance meter?. Surviving mice were sacrificed at P60 for histological analysis. Sections through the hippocampus were stained with cresyl violet and zinc (Timm) histochemistry, and immunocytochemistry for the zinc transporter ZnT3 and GFAP. RESULTS: The average ages at spontaneous death (from recurrent seizures or status epilepticus) in -/- mice were 44.7 ? 1.7 and >56.9 ? 1.7 days for normal and KD treatments, respectively (p=0.002); 3 of 33 control and 6 of 10 KD mice survived to P60. BHB levels in KD-treated mice were elevated over controls in surviving mice. As compared to wild-type animals, Kv1.1 -/- mice treated with a standard diet demonstrated increased Timm labeling in the dentate gyrus and increased GFAP expression throughout the hippocampus by P60. In preliminary experiments, KD-treated -/- mice exhibited greater GFAP immunoreactivity in the hippocampus, and less ZnT3 labeling or Timm staining in the inner molecular layer of the dentate gyrus, as compared to -/- mice on a standard diet. CONCLUSIONS: An experimental KD enhances the survivability of severe, epileptic Kv1.1 -/- mice, and appears to reduce synaptic reorganization of dentate granule cells. These findings suggest that a KD may affect long-term structural alterations that may accompany chronic seizure activity. [Supported by NIH grants K08 NS 01974 (JMR), NS18895 (PAS), and DC/NS02739 (BLT)].