Low blood glucose precipitates spike‐and‐wave activity in genetically predisposed animals

Summary Purpose:   Absence epilepsies are common, with a major genetic contribution to etiology. Certain environmental factors can influence absence occurrence but a complete understanding of absence precipitation is lacking. Herein we investigate if lowering blood glucose increases spike‐wave activity in mouse models with varying seizure susceptibility. Methods:   Three mouse models were used: an absence seizure model based on the knockin of a human GABA A γ2(R43Q) mutation (DBA(R43Q)), the spike‐wave discharge (SWD)–prone DBA/2J strain, and the seizure resistant C57Bl/6 strain. Electrocorticography (ECoG) studies were recorded to determine SWDs during hypoglycemia induced by insulin or overnight fasting. Key Findings:   An insulin‐mediated reduction in blood glucose levels to 4 m m (c.a. 40% reduction) was sufficient to double SWD occurrence in the DBA(R43Q) model and in the SWD‐prone DBA/2J mouse strain. Larger reductions in blood glucose further increased SWDs in both these models. However, even with large reductions in blood glucose, no discharges were observed in the seizure‐resistant C57Bl/6 mouse strain. Injection of glucose reversed the impact of insulin on SWDs in the DBA(R43Q) model, supporting a reduction in blood glucose as the modulating influence. Overnight fasting reduced blood glucose levels to 4.5 m m (c.a. 35% reduction) and, like insulin, caused a doubling in occurrence of SWDs. Significance:   Low blood glucose can precipitate SWDs in genetically predisposed animal models and should be considered as a potential environmental risk factor in patients with absence epilepsy.