Acute and Chronic Respiratory Effects from Repeated Audiogenic Seizures in SSKcnj16−/− Rats

Abstract

Kir5.1 is a member of an inwardly rectifying potassium (Kir) channel family highly expressed in the kidney and brain. Mutations in ion channel genes can alter neuronal excitability, and mutations in related Kir genes have been linked to seizure disorders in humans. We previously established that a knockout rat model of Kcnj16 (gene encoding Kir5.1) on a Dahl salt‐sensitive background (SSKcnj16−/−) exhibits a severe cardiovascular phenotype (Palygin et al., JCI Insight, 2017) as well as an audiogenic reflex epilepsy phenotype. SSKcnj16−/− rats, but not control SS rats, experience tonic‐clonic seizures when exposed to a 10 kHz tone (86 dB for 2 min). Although seizures are typically considered benign events, patients with uncontrolled epilepsy are 27 times more likely die of Sudden Unexplained Death in Epilepsy (SUDEP) compared to those without epilepsy, presumably due to cardiorespiratory failure associated with repeated seizures. Here, we tested the hypothesis that repeated audiogenic seizures would acutely and chronically alter breathing in SSKcnj16−/− but not control SS rats. SSKcnj16−/− and control rats were exposed to the acoustic stimulus once/day for 10 days while using plethysmography to measure breathing before, during, and after exposure. SSKcnj16−/− rats show a marked increase in tidal volume (1.4 ± 0.1 to 3.2 ± 1.2 mL/100g) after acoustic stimulation which becomes more pronounced after exposure to 10 acoustic stimuli (1.7 ± 0.1 to 4.2 ± 1.1 mL/100g). Minute ventilation and drive to breathe show similar increases with successive acoustic exposures. SS control rats do not show changes in tidal volume or minute ventilation over the 10 days. In addition, we see a substantial increase in resting VO2 between day 1 (7.4 ± 0.4 mL/min/100g) and day 10 (11.8 ± 0.6 mL/min/100g) of acoustic stimulation in SSKcnj16−/−/− rats but not controls. During the 10 days of stimulation, we observed spontaneous mortality in 33% of SSKcnj16−/− rats (N = 7 of 21 total) within hours of a seizure, while 100% (N=12) of control SS rats survived. We found no difference among male and female SSKcnj16−/− rats, where both sexes had a similar audiogenic seizure response and reduced survival. Further studies into the mechanisms behind seizure‐induced death in SSKcnj16−/− rats could have central relevance to the pathophysiology of SUDEP, which remains poorly understood.Support or Funding InformationNIH HL122358This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.