Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with intractable epilepsy. SUDEP frequently occurs at night, presumably during sleep, but the mechanisms for how this happens are not well understood. Recently, we demonstrated in the maximal electroshock seizures (MES), an acute seizure model, that vigilance state can impact seizure propensity, seizure severity, the effects of seizures on breathing and whether or not a seizure will be fatal. We also previously showed in the same model that serotonin can influence these measures. The MES model is a model of acute seizures in a seizure-naﶥ brain, and not necessarily a model of epilepsy. Here we aimed to determine vigilance state and serotonin similarly influence seizure susceptibility, severity, survival, and cardio-respiratory consequences of seizures in two established models of epilepsy in which the brain is rendered hyperexcitable ?" amygdala kindling and pilocarpine-temporal lobe epilepsy. Methods: EEG, EMG and EKG electrodes were implanted in adult male wildtype (WT) and serotonin neuron deficient (Lmx1bf/f/p) mice with or without a bipolar stimulating/recording electrode in the right amygdala. Seizures were induced with amygdala kindling (80-240 ?A, 1 ms biphasic square wave, 1 s, 60 Hz, twice daily stimulations until fully kindled) during wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. EEG, EMG, and EKG, were recorded, and breathing was assessed via whole body plethysmography. Vigilance state was determined on-line in real time based on EEG, EMG and behavioral characteristics using standard parameters. All vigilance states were verified post-hoc. A separate set of animals were made to spontaneously seize with pilocarpine (275-400 mg/kg, i.p.) induced status epilepticus and epileptogenesis. For these animals, seizures were analyzed post-hoc for vigilance state of occurrence and effects on breathing and cardiac activity were assessed. Results: Seizures induced during NREM in the kindling model were associated with increased respiratory rate variability and increased occurrence of apneas in both genotypes. Seizures were not readily induced during REM in the kindling model in WT mice, but could be induced during REM in Lmx1bf/f/p mice. Seizures occurred rarely during REM in WT mice the spontaneously seizing model, but occurred much more frequently in Lmx1bf/f/p mice. Conclusions: These data indicate that seizures that occur during sleep in animal models of epilepsy can have detrimental effects on breathing, which may contribute to increased seizure related death, and that serotonin may be involved in vigilance state dependent regulation of seizure occurrence. Funding: NIH/NINDS K08NS069667; NIH/NINDS R01NS095842; Citizens United for Research in Epilepsy (CURE)