Abstracts

Rationale: The occurrence of seizures in epilepsy sometimes follow circadian or multi-day patterns. The mechanisms underlying this rhythmicity are incompletely understood. Here we used a translationally relevant rat model of mesial temporal lobe epilepsy (MTLE) – the intrahippocampal methionine sulfoximine (MSO) infusion model – to study the relationship between seizure occurrence and rhythmic oscillations in extracellular brain chemistry levels. Methods: MSO was chronically infused into one of the hippocampi to induce MTLE, as described previously. PBS infused animals were used as controls. Video-intracranial EEG was continuously recorded over 21 days and microdialysis samples were collected in 1 h aliquots from both hippocampi for up to 7 days. Glutamate, GABA, leucine, isoleucine and valine were quantified in the microdialysis samples using liquid chromatography-tandem mass spectrometry. The distribution of seizures vs time was tested for non-uniformity using the chi-square statistic. We assessed for significant periodicity in brain chemistry levels within a time window of 20 to 28 h using the JTK_CYCLE algorithm in R software (version: 3.6.0). Bonferroni and Benjamini–Hochberg corrections were used to adjust for multiple comparisons. Results: 1,535 seizures were observed in 23 epileptic rats. When plotted over the 24 h day the analysis revealed a distinct cyclical pattern (p < 0.0001). GABA showed significant periodicity in the MSO-infused (P = 24 h; p < 0.001) and non-infused (contralateral) hippocampus (P = 24 h; p < 0.01) as well as in the PBS-infused hippocampus (P = 27 h; p<0.001). Glutamate (P = 28 h; p<0.05), valine (P = 28 h; p<0.001) and isoleucine (P = 27 h; p<0.01) showed significant periodicity only in the MSO-infused hippocampus. Leucine did not show significant periodicity in any animals. Conclusions: The MSO model of MTLE is characterized by significant circadian patterns in seizure frequency, making this a relevant model for mechanistic studies of seizure periodicity. Several neurochemicals exhibited intriguing periodic oscillations, suggesting a possible link between specific brain chemistry fluctuations and cyclic changes in seizure occurrence. Funding: Swebilius Foundation