Time-of-day influences on respiratory sequelae following maximal electroshock-induced seizures in mice

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Although specific mechanisms underlying SUDEP are not well understood, evidence suggests most SUDEP occurs due to seizure-induced respiratory arrest. SUDEP also tends to happen at night. Although this may be due to circumstances in which humans find themselves at night, such as being alone without supervision or sleeping prone, or to independent influences of sleep state, there are a number of reasons why the night (i.e., circadian influences) could be an independent risk factor for SUDEP. We explored this possibility. Adult male WT mice were instrumented for EEG, EMG, and EKG recording and subjected to maximal electroshock (MES) seizures during wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep during the nighttime/dark phase. These data were compared with data collected following seizures induced during the daytime/light phase. Seizures induced during the nighttime were similar in severity and duration to those induced during the daytime; however, seizures induced during the nighttime were associated with a lesser degree of respiratory dysregulation and postictal EEG suppression. Seizures induced during REM sleep during the nighttime were universally fatal, as is seen when seizures are induced during REM during the daytime. Taken together, these data implicate a role for time of day in influencing the physiological consequences of seizures that may contribute to seizure-induced death. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP frequently occurs during the night, which has been attributed to an effect of sleep. We have shown that sleep state does indeed influence survival following a seizure. That SUDEP occurs during the night could also implicate a circadian influence. In this study we found that time of day independently affects the physiological consequences of seizures.

Effect of monoamine reuptake inhibition and α1 blockade on respiratory arrest and death following electroshock‐induced seizures in mice

“…Mice were housed in cages in a 12-hour light/12-hour dark schedule with food and water available ad libitum. Breeding and genotyping of Lmx1b f/f and Lmx1b f/f/p mice has been described previously 27,28. Briefly, Lmx1b f/f mice carry 2 floxed…”

Post-ictal generalized EEG suppression and seizure-induced mortality are reduced by enhancing dorsal raphe serotonergic neurotransmission

“…Similarly, pre-seizure application of acidified aCSF to the DRN or optogenetic stimulation of DRN 5-HT neurons decreased PGES duration in kindled mice. In the MES model, PGES duration and mortality is greater following seizures induced during NREM sleep (Hajek and Buchanan, 2016;Purnell, et al, 2017). Our results indicate that acidosis of the DRN reduced mortality following MES seizures induced from wake.…”

“…On trial days the ear-clip electrodes were attached to the mice and plugged into a Rodent Shocker pulse generator (D-79232; Harvard Apparatus). After a 30 min habituation period, a single 50 mA (0.2 s, 60 Hz sine wave pulses) stimulus was administered during wake to induce a maximal hindlimb extension seizure (Buchanan, et al, 2014;Hajek and Buchanan, 2016;Purnell et al, 2017). Mortality, seizure duration, and extension-to-flexion ratios (E/F ratios) were determined post-hoc using EEG/EMG monitoring and video assessments.…”

“…To determine whether stimulation of DRN neurons with acidosis could also reduce mortality, DRN neurons were stimulated with acidified aCSF for 10 min prior to seizure induction via MES, a model with known mortality (Buchanan, et al, 2014;Hajek and Buchanan, 2016;Kruse et al, 2019;Li and Buchanan, 2019;Purnell, et al, 2017). Perfusion of acidified aCSF into the DRN prior to MES induced seizures reduced mortality (4 survived vs 2 died; acidosis: n = 6; normal: n = 6; p < 0.05; Fig.…”

Dead in the Night: Sleep-Wake and Time-Of-Day Influences on Sudden Unexpected Death in Epilepsy

“…Seizures induced by MES during the day, the rodent inactive phase, are similar to seizures induced during the night in terms of duration and severity; however, MES seizures induced in the day during sleep resulted in a greater degree of postictal respiratory suppression (Figure 3, (134)). Seizures induced during this time also resulted in prolonged EEG suppression.…”