Acute and chronic effects of seizures on cardiorespiratory control in the SSKcnj16-/- rat

Abstract

Epilepsy is a common neurological disorder in which 1/3rd of patients experience repeated seizures, putting them at greater risk for Sudden Unexpected Death in Epilepsy (SUDEP). A leading hypothesis based on human data suggests severe post-ictal cardiorespiratory suppression precedes a SUDEP event. However, the pathophysiological consequences of repeated seizures on cardiorespiratory control/function remain unclear. Our lab has previously established a rat model harboring an 18 bp-mutation in the Kcnj16 gene (encoding Kir5.1 channel; SSKcnj16-/- rats), which is susceptible to sound-induced (audiogenic) seizures. In this model, repeated seizures (1/day for 10 days) lead to ictal apnea, post-ictal respiratory suppression, blunted chemoreflexes, and spontaneous mortality. While the respiratory effects of repeated seizures in our rat model have been established, the cardiorespiratory sequence of events leading to a SUDEP-like event remain unknown. Here we test the hypothesis that repeated seizures in SSKcnj16-/- rats result in cardiorespiratory dysfunction and lead to a sequence of pathological events accompanying human SUDEP. Male and female SSKcnj16-/- rats (n=5,6) were surgically implanted with radiotelemetry pressure devices and allowed >3 days to recover. The rats were then housed in a custom-made plethysmograph for long-term housing to measure breathing, blood pressure (BP), heart rate (HR), and behavior continuously for 10 days (d). The rats were exposed to a sound stimulus (2 min) to elicit a seizure once/d for 10d. As reported previously, audiogenic seizures caused ictal apneas and transient post-ictal respiratory frequency depression. However, for the first time, we also found ictal asystole and dramatic decreases in HR but increases in BP for ~20 min after seizures. These acute effects of seizures on breathing and HR/BP appear to be exaggerated with increasing numbers of seizures throughout the 10d protocol. In addition, we captured during the 10d protocol SUDEP-like events in six out of eleven SSKcnj16-/- rats studied. Unlike most experiments that showed recovery of cardiorespiratory measures within ~30 min, SSKcnj16-/- rats with a terminal event had reduced ventilation due to a reduced tidal volume, and BP steadily declined with minimal effects on HR in the 2-5 hours preceding death (n=4). Our preliminary data suggest repeated seizures induce acute cardiorespiratory disruptions which in some cases can lead to a SUDEP-like event in SSKcnj16-/- rats characterized by suppressed tidal volume, hypopnea and time-dependent hypotension. Funded by NIH HL122358 (MRH), DK126720 (OP), and HL135749 (AS). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.