Serotonin neurones have anti‐convulsant effects and reduce seizure‐induced mortality

Abstract

Key pointsr Sudden unexpected death in epilepsy is the leading cause of death in patients with refractory epilepsy.r Respiratory and cardiac impairment induced by a seizure have been identified as possible causes of seizure-related death, but which is more important has been the subject of debate.r Serotonin has been linked to seizure control, but whether it is primarily anti-convulsant or proconvulsant remains controversial.r In this study we induced seizures in mice with a genetic deletion of serotonin neurones and their phenotypically normal littermates while recording EEG, EMG, ECG and breathing, and assessed the effects of seizures on breathing, cardiac activity and survival r Serotonin and serotonin neurones are involved in setting the seizure threshold, regulating seizure severity and preventing mortality, and death in at least one seizure model is due to respiratory arrest, which can be prevented with selective serotonin reuptake inhibitor treatment or 5-HT 2A receptor activation.Abstract 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-HT 2A 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.

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…Notably, the EEG rapidly became flat after the seizure, consistent with PGES (25). This same observation was reported previously after maximal electroshock (MES) induced seizures in Lmx1b f/f/p mice, which lack over 99% of 5-hydroxytryptamine (5-HT) neurons in the CNS (19).…”

“…It is not known whether BSD occurs in our model. PGES always occurred in Scn1a R1407X/+ mice that died, as was previously reported in Lmx1b f/f/p mice after MES seizures (19). BSD, PGES, and apnea could all be reflective of some underlying causative mechanism.…”

“…High-dose systemic atropine did not reduce the duration or severity of heat-induced seizures as determined by EEG analysis or decrease the likelihood of Racine scale 5 seizures, but it did decrease the likelihood of tonic hind limb extension, suggesting there were effects on forebrain seizure activity. It is not known whether an effect on seizures in the forebrain protected against apnea or whether protection was due to inhibition of forebrain projections to the brain stem or to , DBA, and 5-HT 2c knockout mice (19,21,76). For a seizure to induce apnea, forebrain activity must propagate to the lower brain stem where breathing is controlled.…”

“…A variety of mechanisms have been proposed for SUDEP (1,2,(4)(5)(6), including cardiac arrhythmias (7)(8)(9)(10), dysfunction of autonomic control (11)(12)(13)(14)(15), apnea/hypoventilation (3,(16)(17)(18)(19)(20)(21), airway obstruction (22), pulmonary edema (23), brain stem spreading depolarization (BSD) (24), and postictal generalized EEG suppression (PGES) (25). Many investigators have focused on cardiac tachyarrhythmias as the cause of death, in part because of an association between SUDEP and mutations of genes expressed in the heart, such as those that underlie long QT syndrome (10,(26)(27)(28).…”

Citalopram as a good candidate for treatment of depression in patients with epilepsy

“…Therefore, targeting 5-HT 1 /5-HT 3 receptors by citalopram could be one mechanism for its antiepileptic effects [16,17]. Interestingly, a very recent report proposed that citalopram prevents sudden unexpected death in epilepsy by affecting 5-HT 2 receptors in mice [18]. Furthermore, the alteration in paired-pulse inhibition of the epileptic hippocampus induced by citalopram may be mediated by GABAergic transmission [19].…”