Jun Wang, Jesse Isaacson, Anna Goforth, Rama Maganti
Susceptibility to epileptogenesis varies in humans and mouse strains. We hypothesized that baseline sleep abnormalities increase susceptibility to epileptogenesis following Kainic acid (KA) and that abnormalities in diurnal rhythm or sleep homeostasis (SH) contribute to worse seizure outcomes. 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 electroencephalography (EEG). Seizures were manually scored and interictal spikes and sleep were analyzed using machine learning algorithms. Slow wave activity (SWA-05-4 Hz) 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. Seizures were longer and more frequent in KA-treated DBAs than C57s. Interictal spike-like events were much greater in saline-treated DBAs than C57s. DBAs had lower SWA at baseline. KA treatment decreased REM and increased SWA activity in DBAs. Cosinor analysis revealed diurnal rhythm abnormalities in DBAs but not in C57s. Following seizures in DBAs, abnormalities in SH markers were seen including failure of SWA to rise with preceding wakefulness and a progressive loss of SWA decay during lights-on across the weeks. The findings suggest that baseline sleep abnormalities, poorly adaptable diurnal rhythms and impaired SH may be associated with increased vulnerability to epileptogenesis. Therapies enhancing diurnal rhythm and SH after an insult may be avenues to mitigate epileptogenesis in vulnerable populations.