Sudden unexpected death in epilepsy (
SUDEP) is the leading cause of death in patients with
refractory epilepsy. Defects in central control of breathing are important contributors to the pathophysiology of
SUDEP, and
serotonin (5-HT) system dysfunction may be involved. Here we examined the effect of
5-HT neurone elimination or
5-HT reduction on seizure risk and seizure-induced mortality. Adult Lmx1b(f/f/p) mice, which lack >99% of
5-HT neurones in the CNS, and littermate controls (Lmx1b(f/f)) were subjected to acute seizure induction by maximal electroshock (MES) or
pilocarpine, variably including electroencephalography, electrocardiography, plethysmography,
mechanical ventilation or pharmacological
therapy. Lmx1b(f/f/p) mice had a lower seizure threshold and increased seizure-induced mortality. Breathing ceased during most
seizures without recovery, whereas cardiac activity persisted for up to 9 min before terminal arrest. The mortality rate of mice of both genotypes was reduced by
mechanical ventilation during the seizure or
5-HT2A receptor agonist pretreatment. The
selective serotonin reuptake inhibitor citalopram reduced mortality of Lmx1b(f/f) but not of Lmx1b(f/f/p) mice. In C57BL/6N mice, reduction of
5-HT synthesis with
para-chlorophenylalanine increased MES-induced seizure severity but not mortality. We conclude that
5-HT neurones raise seizure threshold and decrease seizure-related mortality. Death ensued from
respiratory failure, followed by terminal
asystole. Given that
SUDEP often occurs in association with generalised
seizures, some mechanisms causing death in our model might be shared with those leading to
SUDEP. This model may help determine the relationship between
seizures,
5-HT system dysfunction, breathing and death, which may lead to novel ways to prevent
SUDEP.