Faculty Collaboration Database

Repeated seizures lead to progressive ventilatory dysfunction in SS^Kcnj16-/- rats. J Appl Physiol (1985) 2023 Oct 01;135(4):872-885

Date

08/03/2023

Pubmed ID

37535709

Pubmed Central ID

PMC10642517

DOI

10.1152/japplphysiol.00072.2023

Scopus ID

2-s2.0-85174642163 (requires institutional sign-in at Scopus site)

Abstract

Patients with uncontrolled epilepsy experience repeated seizures putting them at increased risk for sudden unexpected death in epilepsy (SUDEP). Data from human patients have led to the hypothesis that SUDEP results from severe cardiorespiratory suppression after a seizure, which may involve pathological deficiencies in the brainstem serotonin (5-HT) system. Rats with a genomic Kcnj16 mutation (SS^Kcnj16-/- rats) are susceptible to sound-induced generalized tonic-clonic seizures (GTCS) which, when repeated once daily for up to 10 days (10-day seizure protocol), increased mortality, particularly in male rats. Here, we test the hypothesis that repeated seizures across the 10-day protocol will cause a progressive ventilatory dysfunction due to time-dependent 5-HT deficiency. Initial severe seizures led to ictal and postictal apneas and transient decreases in breathing frequency, ventilatory drive, breath-to-breath variability, and brief hypoventilation. These seizure-induced effects on ventilation were exacerbated with increasing seizures and ventilatory chemoreflexes became further impaired after repeated seizures. Tissue analyses of key brainstem regions controlling breathing showed time-dependent 5-HT system suppression and increased immunoreactivity for IBA-1 (microglial marker) without changes in overall cell counts at 3, 7, and 10 days of seizures. Fluoxetine treatment in SS^Kcnj16-/- rats prevented repeated seizure-induced progressive respiratory suppression but failed to prevent seizure-related mortality. We conclude that repeated seizures cause a progressive compromise of ventilatory control in the immediate postictal period largely mediated by serotonin system suppression in brainstem regions of respiratory control. However, other unknown factors contribute to overall survival following repeated seizures in this model.NEW & NOTEWORTHY This study demonstrated that repeated seizures in a novel rat model (SS^Kcnj16-/- rats) caused a progressively greater ventilatory dysfunction in the immediate postictal period associated with brainstem serotonin (5-HT) suppression. Augmenting brain 5-HT with a selective serotonin reuptake inhibitor prevented the progressive ventilatory dysfunction induced by repeated seizures but failed to prevent seizure-related mortality, suggesting that repeated seizures may lead to cardiorespiratory suppression and failure through multiple mechanisms.

Author List

Manis AD, Cook-Snyder DR, Duffy E, Osmani WA, Eilbes M, Dillard M, Palygin O, Staruschenko A, Hodges MR

Authors

Denise R. Cook-Snyder PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Matthew R. Hodges PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Death, Sudden
Electroencephalography
Humans
Male
Rats
Seizures
Serotonin