Sleep dynamics and epileptogenesis following Kainic acid in epilepsy-susceptible (DBA/2J) and epilepsy-resistant (C57BL/6) mice

Susceptibility to epileptogenesis varies in humans and outbred mouse strains. We hypothesized that baseline sleep abnormalities increase susceptibility to epileptogenesis following Kainic acid (KA) and abnormal circadian rhythm or sleep homeostasis (SH) contribute to worse seizures in epilepsy-susceptible DBAs. Following EEG electrode implantation, C57 and DBA mice underwent repeated low-dose KA or saline treatment. Seizures, interictal spikes and sleep were examined over 8-weeks with continuous electroencephalography (EEG). Seizures were manually scored, and interictal spikes and sleep were analyzed using machine learning algorithms. Slow wave activity (SWA) was derived from non-rapid eye movement (NREM) sleep following Fourier transform, and SH was measured by the decay of SWA during sleep and its rise with preceding wakefulness. The impact of post-KA seizures on circadian rhythm was determined using Cosinor analysis. Seizures were longer and more frequent in KA-treated DBAs than C57s. Interictal spike were much greater in saline-treated DBAs than C57s. SWA across the 24-hours was lower in DBAs at baseline. KA treatment decreased REM and increased SWA activity in DBAs but not in C57s. Cosinor analysis revealed circadian rhythm abnormalities in DBAs but not in C57s. Seizures impaired SH in DBAs, with no increase in SWA with preceding wakefulness and a progressive loss of SWA decay during lights-on over the 8-week recording. These findings suggest that baseline sleep abnormalities, poorly adaptable circadian rhythms and impaired SH are associated with increased vulnerability to epileptogenesis. Therapies enhancing circadian rhythm and SH after an insult may be avenues to mitigate epileptogenesis in vulnerable populations.