Journal article
Seizures cause prolonged impairment of ventilation, CO2 chemoreception and thermoregulation
The Journal of neuroscience, Vol.43(27), pp.4959-4971
07/05/2023
DOI: 10.1523/JNEUROSCI.0450-23.2023
PMCID: PMC10324997
PMID: 37160367
Abstract
Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1aR1407X/+ (Dravet Syndrome, DS) and Scn8aN1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a post-ictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe post-ictal depression of the HCVR also exhibited transient post-ictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-Hydroxytryptamine, 5-HT) system in mice. Depleting 5-HT with para-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the post-ictal decrease in the HCVR, exacerbated hypothermia, and increased post-ictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced post-ictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the inter-ictal and/or post-ictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing post-ictal 5-HT tone.
Details
- Title: Subtitle
- Seizures cause prolonged impairment of ventilation, CO2 chemoreception and thermoregulation
- Creators
- Frida A Teran - University of IowaRup K Sainju - University of IowaEduardo Bravo - University of IowaJacy Wagnon - University of Michigan–Ann ArborYuJaung Kim - University of IowaAlex Granner - University of IowaBrian K Gehlbach - University of IowaGeorge B Richerson - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.43(27), pp.4959-4971
- DOI
- 10.1523/JNEUROSCI.0450-23.2023
- PMID
- 37160367
- PMCID
- PMC10324997
- eISSN
- 1529-2401
- Grant note
- DOI: 10.13039/100000065, name: HHS | NIH | National Institute of Neurological Disorders and Stroke, award: U01 NS090414, U01 NS090407, R01 NS123155, F31 NS110333, R01 NS113764; name: Beth & Nate Tross Epilepsy Research Fund
- Language
- English
- Electronic publication date
- 05/08/2023
- Date published
- 07/05/2023
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Iowa Neuroscience Institute; Neurosurgery; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984406603902771
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