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- Title
Seizures Cause Prolonged Impairment of Ventilation, CO<sub>2</sub> Chemoreception and Thermoregulation.
- Authors
Teran, Frida A.; Sainju, Rup K.; Bravo, Eduardo; Wagnon, Jacy; YuJaung Kim; Granner, Alex; Gehlbach, Brian K.; Richerson, George B.
- 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 (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1aR1407X/1 (Dravet syndrome; DS) and Scn8aN1768D/1 (D/1) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal 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 postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal 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 interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone.
- Subjects
SEROTONIN syndrome; CHEMICAL senses; VENTILATION; EPILEPSY; BODY temperature regulation; SEIZURES (Medicine); SUDDEN death
- Publication
Journal of Neuroscience, 2023, Vol 43, Issue 27, p4959
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0450-23.2023