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Apnea associated with brainstem seizures in Cacna1a S218L mice is caused by medullary spreading depolarization.

Research paper by Nico A NA Jansen, Maarten M Schenke, Rob A RA Voskuyl, Roland D RD Thijs, Arn M J M AMJM van den Maagdenberg, Else A EA Tolner

Indexed on: 21 Oct '19Published on: 20 Oct '19Published in: The Journal of neuroscience : the official journal of the Society for Neuroscience



Abstract

Seizure-related apnea is common and can be lethal. Its mechanisms however remain unclear and preventive strategies are lacking. We postulate that brainstem spreading depolarization (SD), previously associated with lethal seizures in animal models, initiates apnea upon invasion of brainstem respiratory centers. To study this, we assessed effects of brainstem seizures on brainstem function and respiration in male and female mice carrying a homozygous S218L missense mutation that leads to gain-of-function of voltage-gated Ca2.1 Ca channels and high risk for fatal seizures. Recordings of brainstem DC potential and neuronal activity, cardiorespiratory activity and local tissue oxygen were performed in freely behaving animals. Brainstem SD occurred during all spontaneous fatal seizures and, unexpectedly, during a subset of non-fatal seizures. Seizure-related SDs in the ventrolateral medulla correlated with respiratory suppression. Seizures induced by stimulation of the inferior colliculus could evoke SD that spread in a rostro-caudal direction, preceding local tissue hypoxia and apnea, indicating that invasion of SD into medullary respiratory centers initiated apnea and hypoxia rather than Fatal outcome was prevented by timely resuscitation. Moreover, NMDA receptor antagonists MK-801 and memantine prevented seizure-related SD and apnea, which supports brainstem SD as a prerequisite for brainstem seizure-related apnea in this animal model and has translational value for developing strategies that prevent fatal ictal apnea.Apnea during and following seizures is common, but also likely implicated in sudden unexpected death in epilepsy (SUDEP). This underlines the need to understand mechanisms for potentially lethal seizure-related apnea. In the present work we show, in freely behaving SUDEP-prone transgenic mice, that apnea is induced when spontaneous brainstem seizure-related spreading depolarization (SD) reaches respiratory nuclei in the ventrolateral medulla. We show that brainstem seizure-related medullary SD is followed by local hypoxia and recovers during non-fatal seizures, but not during fatal events. NMDA receptor antagonists prevented medullary SD and apnea, which may be of translational value. Copyright © 2019 the authors.