Abstracts

Rationale:
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. While the exact etiology of SUDEP remains unclear, it is believed the ultimate cause of death is respiratory failure. A large body of evidence has implicated serotonin (5-HT) in SUDEP. 5-HT is important in the modulation of breathing and plays a role in regulating seizure threshold and severity. Since seizures can reduce 5-HT, we hypothesized that enhancing 5-HT neurotransmission prior to seizure onset would increase respiratory rate (RR), tidal volume (VT) and minute ventilation (VE) and decrease the instance of ictal / postictal apnea. As SUDEP often occurs at night, and 5-HT tone is sleep-state dependent, seizures were induced during both wake and NREM sleep. Because 5-HT2A and 5-HT2C receptors are implicated in setting seizure threshold and severity, agonists for these receptors were also utilized.
Method:
Adult (8-12 weeks) male and female C57BL/6J mice were instrumented for EEG/EMG recording and stereotaxically implanted with a bipolar stimulating/recording electrode into the right basolateral amygdala [AP: -1.3; ML: -2.8; DV: -4.7] for kindling. After recovery from surgery, afterdischarge threshold determination, and kindling, seizures were induced during wake and NREM sleep following treatment with selective 5-HT reuptake inhibitors (SSRI) or 5-HT2 receptor agonists.
Results:
We found that the SSRI citalopram eliminated ictal and postictal apneas, and the SSRI fluoxetine decreased the incidence of apnea when seizures were induced during both wake and NREM sleep. There was no decrease in apneas when animals received the 5-HT2C receptor agonist MK-212 or the 5-HT2A receptor agonist TCB-2. Alternatively, MK-212 but not SSRIs caused an increase in postictal VT and RR. All 5-HT manipulations except for TCB-2 increased breathing regularity following seizures induced during both wake and NREM sleep. In order to determine whether activation of 5-HT2 receptors is necessary for the effect of citalopram on apneas and breathing regularity, a separate cohort of animals received either the 5-HT2A antagonist ketanserin or the 5-HT2C antagonist RS-102221 in conjunction with citalopram.
Conclusion:
Our results indicate that increasing endogenous 5-HT and activation of 5-HT2 receptors cause distinct changes in postictal respiration that do not appear to be sleep state-dependent.
Funding:
:NIH/NINDS R01 NS095842; Beth L. Tross Epilepsy Professorship; Pre-doctoral Fellowship from the American Epilepsy Society/LivaNova, PLC (A.N.P).