Impaired Serotonergic Brainstem Function during and after Seizures

Abstract

Impaired breathing, cardiac function, and arousal during and after seizures are important causes of morbidity and mortality. Previous work suggests that these changes are associated with depressed brainstem function in the ictal and post-ictal periods. Lower brainstem serotonergic systems are postulated to play an important role in cardiorespiratory changes during and after seizures, whereas upper brainstem serotonergic and other systems regulate arousal. However, direct demonstration of seizure-associated neuronal activity changes in brainstem serotonergic regions has been lacking. Here, we performed multiunit and single-unit recordings from medullary raphe and midbrain dorsal raphe nuclei in an established rat seizure model while measuring changes in breathing rate and depth as well as heart rate. Serotonergic neurons were identified by immunohistochemistry. Respiratory rate, tidal volume, and minute ventilation were all significantly decreased during and after seizures in this model. We found that population firing of neurons in the medullary and midbrain raphe on multiunit recordings was significantly decreased during the ictal and post-ictal periods. Single-unit recordings from identified serotonergic neurons in the medullary raphe revealed highly consistently decreased firing during and after seizures. In contrast, firing of midbrain raphe serotonergic neurons was more variable, with a mixture of increases and decreases. The markedly suppressed firing of medullary serotonergic neurons supports their possible role in simultaneously impaired cardiorespiratory function in seizures. Decreased arousal likely arises from depressed population activity of several neuronal pools in the upper brainstem and forebrain. These findings have important implications for preventing morbidity and mortality in people living with epilepsy.

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

“…Serotonin normally plays an important modulatory role in mediating state-dependent changes in the respiratory drive and activity in the brainstem respiratory centers. 49 Deletion of central serotonergic neurons resulted in reduced arousal and deficits in respiratory responses to elevated CO 2 levels in transgenic rodents. These studies also offered evidence for the deleterious interaction between the separate Sz and respiratory networks, which is implicated in the seizure-induced death seen in the DBA/1 mouse model of SUDEP.…”

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…jci.org Volume 128 Number 3 March 2018 prevent apnea, because the neural circuitry involved in generation of respiratory output is contained entirely within the CNS, as are descending projections from the forebrain that cause apnea during and/or after seizures (18,20). Instead, the effect of methylatropine is likely to be due to penetration into the CNS.…”

“…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).…”

Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

“…2,3 Interaction of the seizure network with subcortical structures is proposed to contribute importantly to SUDEP. 6,7 A serotonin hypothesis of SUDEP has been proposed, which postulates that altering serotonergic function significantly modifies susceptibility to seizure-induced sudden death. 6,7 A serotonin hypothesis of SUDEP has been proposed, which postulates that altering serotonergic function significantly modifies susceptibility to seizure-induced sudden death.…”

“…6,7 A serotonin hypothesis of SUDEP has been proposed, which postulates that altering serotonergic function significantly modifies susceptibility to seizure-induced sudden death. 2,3,6,8,10 Human findings also support this hypothesis. 2,3,6,8,10 Human findings also support this hypothesis.…”