Dissertation
The role of serotonin in postictal breathing, arousal, and mortality
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007424
Abstract
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients whose epilepsy is refractory to medication. While the precise pathophysiology underlying SUDEP is unknown, there are several well-documented risk factors for SUDEP. These include (1) periictal respiratory dysfunction, (2) nocturnal seizures, and (3) decreased postictal stimulus-induced arousal, particularly to carbon dioxide (CO2), which is a critical protective reflex. Serotonin (5-HT) plays a major role in breathing, sleep-wake regulation, and CO2-induced arousal. This has led to the speculation that 5-HT circuits are dysregulated by either seizures or epilepsy itself, leading to postictal impairment of breathing and arousal which may result in seizure-induced death.
We hypothesized that 5-HT neuron dysfunction underlies postictal breathing dysfunction and the suppression of postictal CO2-induced arousal, and that pharmacologically increasing 5-HT neurotransmission prior to seizure onset would increase postictal breathing. Preictal administration of selective-serotonin reuptake inhibitors (SSRIs) and 5-HT2 receptor agonists increased several facets of postictal breathing but were ineffective when seizures were induced during sleep. A 5-HT2C receptor agonist caused seizure-induced death in a percentage of animals, but this was due to an off-target effect; potentially relating to an increase in corticosterone. A mouse model of seizures exhibited a decreased arousal response to CO2 postictally but not at baseline. Initial results suggest that seizures cause massive increase in 5-HT neuron activation within the brainstem, followed by a refractory period whereby they were unable respond to CO¬2 for a period of time.
These results suggest that 5-HT neurons are dysregulated by seizures, leading to impairment in postictal breathing and arousal. It is our hope that identifying specific 5-HT circuits that are impacted by epilepsy will inform future interventions to lower SUDEP risk.
Details
- Title: Subtitle
- The role of serotonin in postictal breathing, arousal, and mortality
- Creators
- Katelyn G Joyal
- Contributors
- Gordon F Buchanan (Advisor)George B Richerson (Committee Member)Nandakumar Narayanan (Committee Member)Joseph Glykys (Committee Member)Catherine Marcinkiewcz (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2024
- DOI
- 10.25820/etd.007424
- Publisher
- University of Iowa
- Number of pages
- xi, 157 pages
- Copyright
- Copyright 2024 Katelyn G Joyal
- Grant note
- Thank you to our funding sources: NIH/NINDS F31 NS125955-01 to K.G.J and NIH/NINDS R01 NS095842 and the Beth L. Tross Epilepsy Professorship from the Carver College of Medicine at the University of Iowa to G.F.B. (ii)
- Language
- English
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 138-157).
- Public Abstract (ETD)
- Epilepsy is an extremely common neurological disorder characterized by spontaneous, recurrent seizures. Medication fails to control seizures in more than one third of patients with epilepsy. The leading cause of death in this population is sudden unexpected death in epilepsy (SUDEP). While the exact cause of SUDEP is unclear, impairment in breathing function has been heavily implicated. SUDEP tends to occur during the night, with the victim found face down in bed. This suggests that they were unable to arouse despite rebreathing their expired carbon dioxide (CO2), which is a protective reflex that occurs in a healthy brain. The signaling molecule serotonin (5-HT) plays a major role in breathing, sleep-wake regulation, and CO2-induced arousal. We hypothesized that seizure and epilepsy-induced disruption of 5-HT neuron activity leads to post-seizure breathing dysfunction and suppressed CO2-induced arousal, particularly when seizures occur during sleep. Thus, pretreating animals with drugs that increase 5-HT prior to seizures would facilitate post-seizure breathing. These drugs increased post-seizure breathing and were much less effective when seizures happened during sleep compared to wakefulness. A mouse model of seizures exhibited a decreased arousal response to CO2 following seizures, but not in the absence of a seizure. Initial results suggest that this is due to seizures causing a massive increase in 5-HT neuron activation in the brainstem, which leads to those neurons being “offline” following seizures and thus they are unable respond to CO2 for a period of time. These results suggest that 5-HT neurons are dysregulated by seizures, leading to impairment in post-seizure breathing and arousal. It is our hope that identifying specific 5-HT circuits that are impacted by epilepsy will inform future interventions to lower SUDEP risk.
- Academic Unit
- Interdisciplinary Studies Program
- Record Identifier
- 9984647456402771
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