Abstracts

Rationale: Sudden unexplained death in epilepsy (SUDEP) is a devastating condition in which epilepsy patients die for no apparent reason. It is the leading cause of death among epilepsy patients. Though this has been a long recognized syndrome, there is much to be learned about the pathophysiology of this disease. Cardiac and respiratory etiologies have been implicated to underlie SUDEP. Serotonin (5-HT) is a key regulator of breathing control. 5-HT dysfunction has been implicated in the pathophysiology of SUDEP. Here we employ a mouse model in which nearly all 5-HT neurons have been genetically deleted to determine whether 5-HT neuron absence contributes to seizure-related respiratory dysfunction and death. Methods: EEG, EMG, EKG, body temperature, locomotor activity and breathing were recorded in adult male and female wild type (WT) mice and mice lacking 5-HT neurons (Lmx1b^f/f/p) before, during and after seizure induction via electroshock (1-50 mA, 0.2 s, 60 Hz stimulation via ear electrodes). Seizure susceptibility and mortality were assessed. Seizure severity was scored using the extension-flexion ratio. Results: Seizures induced by electroshock were relatively short (14-33 s) in duration and were comprised of a characteristic brief hind limb flexion followed by hind limb extension as part of the tonic component. The tonic phase was typically followed by a brief clonic phase. Lmx1b^f/f/p mice experienced seizures at slightly lower stimulus intensity (5 mA, 0.2 s, 60 Hz) than WT (10 mA, 0.2 s, 60 Hz). Seizures were more severe, as assessed by the extension-flexion ratio, across stimulus intensities in Lmx1b^f/f/p mice compared to WT mice and in males compared to females. In both genotypes, the tonic phase was always accompanied by respiratory arrest. Seizure-related mortality increased with increasing stimulus intensity and was increased in Lmx1b^f/f/p mice compared to WT mice. There was only a sex difference in mortality at the highest stimulus intensity. Following seizures that ultimately resulted in death, there was an immediate flattening of EEG activity, lack of recovery of spontaneous respirations, and persistence of cardiac activity for up to 6 min following terminal respiration. Cardiac activity became progressively slower, less intense, and more irregular until it ultimately ceased. Conclusions: These results indicate that elimination of central 5-HT neurons renders mice more susceptible to seizure induction and more prone to seizure-related sudden death. These data further indicate that respiratory mechanisms are more directly responsible for death than cardiac arrest and that the 5-HT neuron deficit is responsible for the post-ictal breathing abnormalities