Abnormalities of serotonergic neurotransmission in animal models of SUDEP

Abstract

Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA mice exhibit seizure-induced respiratory arrest (S-IRA), leading to cardiac arrest and subsequent sudden death after generalized audiogenic seizures (AGS). This sequence of terminal events is also observed in the majority of witnessed human SUDEP cases. Several pathophysiological mechanisms, including respiratory/cardiac dysfunction, have been proposed to contribute to human SUDEP. Several (but not all) selective serotonin (5-HT) reuptake inhibitors (SSRIs), including fluoxetine, can reversibly block S-IRA, and abnormal expression of 5-HT receptors is found in the brainstem of DBA mice. DBA mice, which do not initially show S-IRA, exhibit S-IRA after treatment with a non-selective 5-HT antagonist. These studies suggest that abnormalities of 5-HT neurotransmission are involved in the pathogenesis of S-IRA in DBA mice. 5-HT transmission plays an important role in normal respiration, and DBA mice exhibiting S-IRA can be resuscitated using a rodent ventilator. It is important and interesting to know if fluoxetine blocks S-IRA in DBA mice by enhancing respiratory ventilation. To test this, the effects of breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP) were compared to fluoxetine on S-IRA in DBA/1 mice. Although fluoxetine reduces the incidence of S-IRA in DBA/1 mice, as reported previously, the same dose of fluoxetine fails to enhance baseline respiratory ventilation in the absence of AGS. Doxapram and PK-THPP augment the baseline ventilation in DBA/1 mice. However, these breathing stimulants are ineffective in preventing S-IRA in DBA/1 mice. These data suggest that fluoxetine blocks S-IRA in DBA/1 mice by cellular/molecular mechanisms other than enhancement of basal ventilation. Future research directions are also discussed.

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…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).…”

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

“…Compared with the effective breathing stimulant doxapram, which enhanced basal ventilation by ~82%, the enhancement of ventilation by atomoxetine is small. Interestingly, fluoxetine, an SSRI known to reduce S-IRA (Feng and Faingold, 2015), does not enhance basal ventilation in DBA/1 mice (Zeng et al, 2015). Moreover, in our previous study, doxapram and PK-THPP, another potent breathing stimulant, exerted no effect on S-IRA in DBA/1 mice (Zeng et al, 2015).…”

“…Clinical and animal studies demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized tonic-clonic seizures in many cases (Bateman et al, 2008; Blum, 2009; Bravo et al, 2015; Buchanan et al, 2014; Faingold et al, 2010; Langan et al, 2000; Pezzella et al, 2009; Ryvlin et al, 2013; So et al, 2000; Zhang et al, 2016), although cardiac dysfunction may also contribute to seizure-induced sudden death (Frasier et al, 2016; Kalume et al, 2013). Previous studies implicate serotonergic and adenosinergic neurotransmission in the pathogenesis of S-IRA in animal models of SUDEP, including the DBA/1 mouse (Feng and Faingold, 2015; Richerson et al, 2016). Our recent data demonstrate that enhanced norepinephrine (NE) availability in the synapses by intraperitoneal (IP) administration of the NE reuptake inhibitor (NRI) atomoxetine reduces S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice (Zhang et al, 2017).…”

Serotonergic agents act on 5-HT 3 receptors in the brain to block seizure-induced respiratory arrest in the DBA/1 mouse model of SUDEP

“…In the majority of witnessed cases of SUDEP, a generalized convulsive seizure and severe respiratory dysfunction were observed prior to death [3]. DBA/1 and DBA/2 mice have been shown to be relevant models of SUDEP, because they exhibit generalized convulsions that lead directly to seizure-induced respiratory arrest (S-IRA), resulting in death if resuscitation is not rapidly instituted [7–9]. …”