Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in patients with epilepsy. A critical risk factor for SUDEP is repeated generalized tonic-clonic seizures. The mechanism(s) behind SUDEP are almost entirely unknown; however, increasing evidence suggests that apnea (breathing cessation) is the primary cause of death following a seizure in many cases of SUDEP. The two most influential drives to breathe by the brain include descending inputs from forebrain structures and automatic processes coming from brainstem neural circuitry. The brainstem relies on the detection of tissue CO₂ levels to appropriately regulate breathing, a phenomenon known as central CO₂ chemoreception. When forebrain neural activity is reduced, such as during sleep, anesthesia, and certain types of seizures, the drive to breathe relies primarily on CO₂ chemoreception. There is evidence in epilepsy patients that seizures caused a prolonged decrease in the hypercapnic ventilatory response (HCVR), a measurement of CO₂ chemoreception. This has also been replicated in Scn8a^N1768D/+ mice, a mouse model of SCN8A epileptic encephalopathy and SUDEP. In this study, we explore the preictal and postictal HCVR before and after different numbers of induced seizures in Scn8a^N1768D/+ mice.

Methods: We used 8–12-week-old Scn8a^N1768D/+ (referred to here as “D/+”) and wild type littermate control (WT) mice. Audiogenic seizures were induced in D/+ mice using a 15 KHz tone. Body temperature was measured with a surgically implanted telemetric probe (DSI). Whole-body plethysmography (WBP) was used to record preictal and postictal breathing parameters to determine the HCVR. Mice were habituated to the chamber until they were quietly awake, with ~ 200 breaths per minute (bpm). The preictal HCVR was tested by increasing inspired CO₂ from 0% to 3% and then 6%. Next, two audiogenic-induced seizures were evoked, each five minutes apart, and then the postictal HCVR was tested. Minute ventilation was measured as a product of respiratory frequency and tidal volume, and HCVR was determined by the slope of minute ventilation and end-tidal CO₂.

Results: Baseline ventilation and response to 3% and 6% inspired CO2 levels of WT and D/+ mice (Fig. 1) were not different (Fig. 2A; 2-way ANOVA, p = 0.9725). For D/+ mice exposed to two audiogenic seizures, preliminary data suggests that there may be a difference between preictal and postictal HCVR (Fig. 2B, 2C; paired 2-tail t-test, p = 0.1068).

Conclusions: Preliminary data suggests that multiple consecutive seizures can lead to a blunted HCVR. The data can be used to support future experiments examining mechanisms of impaired HCVR and ultimately develop treatments to prevent SUDEP and improve the quality of life for persons with epilepsy.


Funding: NINDS R01 NS133139

Harrison Undergraduate Research Award