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

Abstract

SUMMARYPurpose: 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 spikewave 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 c2(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 mM (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 mM (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.

Multiple molecular mechanisms for a single GABA A mutation in epilepsy

“…We have previously demonstrated that SWD expression is sensitive to background genetics by backcrossing the GABA A g2(R43Q) knock-in model to 2 mouse strains. 5,7 Here we confirm this by showing that the GABA A g2(R43Q) knock-in backcrossed into the C57BL/6J strain (C57) does not have a SWD phenotype ( figure 2, A and B). To test the sensitivity of the febrile seizure phenotype to genetic background, we exposed C57-GABA A g2(R43Q) and DBA-GABA A g2(R43Q) knock-in mice and their wild-type controls to thermogenic stress as described above.…”

“…1,2 By backcrossing the GABA A g2(R43Q) knock-in mouse to strains with different seizure susceptibility, we have demonstrated that the spike-wave phenotype requires additional susceptibility alleles for full expression, 5,7 potentially explaining the low penetrance of absence in the family. In contrast, febrile seizures segregate as a more highly penetrant autosomal dominant trait, which suggests that background genetics have less impact.…”

Pentylenetetrazol-induced seizures strength in diabetic and normal serum glucose elevated male mice

“…The latter finding was in consistent with results of the other literatures. 18,23 The anticonvulsive effect of hyperglycemia, more or less, is a new finding, and recently, have reported in a handful of literatures. 15 Indeed over the years, hyperglycemia were known as unfavorable factor that have increased seizures, but we showed that acute non-diabetic hyperglycemia, by itself, makes animals more resistant against seizure onset, and prevents them to go to more intense phases of the seizures.…”

“…4,6,7 Hyperglycemia and hypoglycemia are two main causes of seizures in which frequently have been seen in diabetes mellitus. 8,9 Epileptic seizure has been reported as the first symptom in 6% diabetic patients and about 19-25% of these patients had periods of seizure in their life. 10 A large body of literature has investigated correlation between hyperglycemia, hypoglycemia and seizure.…”

“…8,[10][11][12][13] However, other investigations have underlined the correlation between hypoglycemia and elevated occurance of epileptic seizures, and report hyperglycemia may has some neurological protective effects. 9,14,15 It is specified that epileptic diabetic patients have had better outcomes if their blood glucose status had been brought under control. 16 Again, there are many clinical evidences that reveal hypoglycemic events lead to seizures.…”