Sequence of physiological events during oxygen conserving reflex activation leading to sudden death in epilepsy

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Project Summary Recent SUDEP research points to serotonin as a key neurotransmitter involved in apnea and death, but most research into serotonin signaling pathways focuses on serotonin signaling in the central nervous system. Our animal experiments modeling SUDEP have shown that the carotid body, a peripheral structure, plays a major role in the progression of fatal apnea. I will explore how peripheral intervention through the carotid body impacts respiration by observing how serotonin and serotonergic compounds affect oxygen conserving reflexes during acute seizure experiments (Aim 1) and using photopharmacology (light-mediated drug delivery) to localize pharmaceutical interventions to the carotid body (Aim 2) in acute seizure experiments with oxygen conserving reflexes. Aim 1 will probe serotonin mechanisms in ictal respiratory crisis from our animal model that we can compare to mechanisms observed in clinical seizure cases. This may further validate the animal SUDEP model and could also imply an effective way to stratify SUDEP risk for patients. Aim 1 will help answer whether promoting serotonin signaling can prevent respiratory failure leading to sudden death. Administering serotonin intracranially and systemically will help explore how seizure affects serotonin signaling pathways and determine whether systemic upregulation of serotonin can mitigate these effects. Similarly, administering serotonergic compounds will provide insight into how pharmaceutical treatments prescribed for other serotonin disorders impact respiration during seizure. Aim 2 will explore how targeted serotonin administration affects respiratory pathways implicated in SUDEP. Photocaged serotonin will enable me to only administer serotonin to a region illuminated with the proper wavelength of light. This will clarify the role of the carotid body in respiratory signaling and, if photorelease of serotonin succeeds in preventing sudden death, this could lead to the development of a chronic device to prevent SUDEP in at-risk patients. In addition to yielding useful, fundamental mechanistic data about how serotonin impacts respiratory crisis, both inside and outside seizure, the techniques used to generate this data also bear clinical translation relevance. The experimental methods developed here may reasonably transition to practical clinical diagnostic and therapeutic strategies.