Epilepsy is one of the most common neurological disorders, and ~1/3 of patients with epilepsy fail to gain seizure control with anti-seizure medications. These patients are at a particularly high risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is thought to result from post-seizure CNS and cardiorespiratory suppression leading to terminal apnea and asystole. While this general sequence of events in SUDEP is well-documented, the mechanisms by which cardiorespiratory control systems fail after some seizures, but not all seizures, remain elusive. We have previously studied the Dahl Salt-Sensitive Kcnj16-/- rat (SSKcnj16-/-) model, which showed after repeated seizures a progressively greater post-ictal cardiorespiratory suppression, seizure-related mortality, and decreased brainstem serotonin (5-HT) immunoreactivity (-ir) within key brainstem regions of cardiorespiratory control. Here, we tested if additional Kcnj16 mutant rat lines (T64I substitution, AA64-68 deletion (M7), or AA64-81 deletion (M8)) in outbred Sprague-Dawley (SD) rats: 1) repeatedly experience audiogenic seizures, and as a consequence 2) show a progressive ventilatory suppression, seizure-induced mortality, and/or decreased brainstem 5-HT-ir, or 3) if pharmacological depletion of 5-HT with 4-Chloro-DL-phenylalanine (PCPA) promotes seizure-induced death (SzID) in these new models. Ventilation (whole-body plethysmography) and seizure severity (Modified Racine Score; HD video) were quantified in male and female SDKcnj16 mutant lines and wild type (WT) rats for 20 min before (baseline (BL)), during (2-minute auditory stimulus), and up to 20 minutes after seizures, which were induced once daily for up to 10 days. In SDKcnj16 variant animals (T64I; n=15, M7; n=10, and M8; n=12), audiogenic seizures were reproducibly induced daily and led to consistent transient post-ictal respiratory changes without any progressive or cumulative effect. In addition, we did not observe SzID in any of the SDKcnj16 mutant lines and no measurable changes in 5-HT-ir were observed within the nucleus ambiguus (NA) or pre-Bötzinger complex (pre-BötC; T64I; n=4, M7; n=4, and M8; n=4) relative to WT animals (n=4). We next tested if PCPA (200 mg/kg i.p.) or vehicle (equivalent volume of saline) administered before and during the 10-day seizure protocol altered ventilatory responses to seizures and/or induced SzID in SD T64I variants, SD WT, SSKcnj16-/-, and SS WT animals. CNS 5-HT depletion with PCPA was confirmed with HPLC analysis of rat brainstems. Preliminary data suggests that PCPA worsens post-ictal breathing in all Kcnj16 mutant lines regardless of genetic background and hastens mortality in SSKcnj16-/- rats but not SDKcnj16 mutant lines. These studies emphasize the critical role of 5-HT system function in mounting an effective post-ictal cardiorespiratory recovery and survival, but also suggests other factors contribute. Funded by NIH HL122358. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Zangl et al. (Fri,) studied this question.