Dissertation
Epilepsy, dietary therapies, and SUDEP: the role of serotonin and CO2 chemoreception
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007218
Abstract
More than one-third of people with epilepsy have inadequate control of seizures despite multiple trials of antiepileptic drugs. Uncontrolled tonic-clonic seizures place patients at high risk of sudden unexpected death in epilepsy (SUDEP), the main cause of mortality in patients with drug-resistant epilepsy. Thus, controlling seizure frequency is currently the only proven preventative strategy. The mechanisms underlying SUDEP are not well understood, but evidence from animal and human studies suggest that most SUDEP is due to seizure-induced respiratory dysfunction. The primary purpose of my project was to determine how seizures disrupt breathing and how this increases the risk for SUDEP, and to provide preclinical data on a novel dietary therapy that protects mouse models of epilepsy from seizure-induced death.Here we found that generalized convulsive seizures in Scn1aR1407X/+ mice, a model of Dravet Syndrome (DS), impair the hypercapnic ventilatory response (HCVR; a measure of CO2 chemoreception) and induce hypothermia. We also found that chemical depletion of serotonin (5- HT) mimicked seizure-induced impairment of respiratory control, exacerbated hypothermia, and increased postictal mortality in DS mice. These results provide evidence that the effects of seizures may be due to impairment of 5-HT neuron function.
We next used Scn8aN1768D/+ (D/+) mice, which harbor a gain-of-function mutation that causes them to have spontaneous convulsive seizures and SUDEP, to characterize the sequence of events that leads from a seizure to death. Similar to our previous report in DS mice, we found that convulsive seizures induced ictal apnea in D/+ mice, and SUDEP occurred when breathing did not resume postictally. We then assessed whether D/+ mice also had defects in CO2 homeostasis by measuring the HCVR and found that it was decreased compared to WT littermates. Our findings indicate that seizure-induced respiratory arrest (S-IRA) rather than cardiac dysfunction is the determining event that causes SUDEP in D/+ mice.
Ketogenic diets (KDs) are high-fat, very low-carbohydrate dietary therapies that have been shown to increase the seizure threshold in multiple models of inducible seizures. We fed DS mice either a KD or a KD supplemented with glucose to prevent ketone body formation and found that both groups of mice had a significant reduction in SUDEP compared to mice fed a control diet. Interestingly, increased survival was not associated with a decrease in seizure frequency. We then used DBA/1 mice, which develop generalized seizures in response to an auditory stimulus, to assess the effect of a KD on S-IRA. We found that KD-treated DBA/1 mice had a delayed onset to S-IRA compared to control, an effect that was maintained even when the KD was supplemented with glucose. Our findings show that a KD was protective against S-IRA in two mouse models, and this effect may be due in part to specific dietary components rather than generation of ketone bodies.
Finally, preliminary data in paraShu flies revealed that their epileptiform phenotype was less severe in mutants raised on a diet containing milk whey compared to those raised on a diet without it. We found that adding whey to a regular mouse diet (WD) greatly reduced the incidence of spontaneous seizures and SUDEP in two mouse models of SUDEP. This rescue effect was associated with increased 5-HT levels in the brain of DS mice. This is important, as 5-HT is known to inhibit seizures and also plays a critical role in control of breathing.
Taken together, these data indicate that interictal and postictal abnormalities of respiratory control play a major role in SUDEP and may be a biomarker for those at highest risk. Moreover, this project addresses the critical need to identify therapies that increase longevity of patients at risk for SUDEP and provides preclinical data on a WD that protects mouse models of epilepsy from seizure-induced death.
Details
- Title: Subtitle
- Epilepsy, dietary therapies, and SUDEP: the role of serotonin and CO2 chemoreception
- Creators
- Frida Angelina Terán
- Contributors
- George B Richerson (Advisor)Gordon F Buchanan (Committee Member)Alexander G Bassuk (Committee Member)Toshihiro Kitamoto (Committee Member)Stephanie C Gantz (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007218
- Publisher
- University of Iowa
- Number of pages
- xvi, 147 pages
- Copyright
- Copyright 2021 Frida Angelina Terán
- Language
- English
- Date submitted
- 04/20/2023
- Date approved
- 06/30/2023
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 126-147).
- Public Abstract (ETD)
Nearly 65 million people worldwide suffer from epilepsy, and about a third of them live with uncontrollable seizures because the existing medications do not work for them. This places them at a high risk for sudden unexpected death in epilepsy (SUDEP), the leading cause of death in people with uncontrolled epilepsy. In SUDEP, no other cause of death is found when an autopsy is done. The reason why SUDEP occurs is not well known. However, there is a growing appreciation of how seizures disrupt breathing, and how this can sometimes be fatal.
The purpose of the experiments in this project was to use mouse models of epilepsy to investigate: 1) how seizures affect respiratory control and the circumstances around them, 2) whether dietary therapies like the ketogenic diet prevent seizure-induced disruption of breathing, and 3) the mechanisms of a novel diet supplemented with milk whey that we found to protect a mouse model of epilepsy from SUDEP. I found that seizures inhibit the ability to augment breathing in response to higher levels of CO2 in mice, which can predispose them to SUDEP. I also found that a whey-supplemented diet is just as effective as a ketogenic diet to prevent SUDEP in two mouse models of epilepsy. Altogether, my findings contribute to a better understanding of why SUDEP occurs and provide preclinical data that may guide future clinical trials to evaluate whey supplementation as an effective dietary therapy for drug-resistant epilepsy.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984428941602771
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