Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice
| Autor: | Piotr Kozlowski, Arn M. J. M. van den Maagdenberg, Maarten Schenke, Inge C.M. Loonen, Else A. Tolner, Michel D. Ferrari, Andrew Yung, Barry Bohnet, Stuart M. Cain, Terrance P. Snutch, Nico A Jansen, Rob A. Voskuyl, Roland D. Thijs |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male mouse model Respiratory arrest semiology Context (language use) Mice Transgenic 03 medical and health sciences Epilepsy Death Sudden Mice 0302 clinical medicine Calcium Channels N-Type spreading depolarization Seizures 1 channels medicine Premovement neuronal activity Animals Humans Cerebral Cortex sudden unexpected death in epilepsy business.industry Cortical Spreading Depression Ca(v)2 Depolarization medicine.disease Scientific Commentaries humanities Clonus Mice Inbred C57BL 030104 developmental biology Excitatory postsynaptic potential Female Neurology (clinical) Brainstem medicine.symptom business Neuroscience 030217 neurology & neurosurgery Brain Stem |
| Zdroj: | Brain, 142, 412-425 |
| Popis: | Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy in which brainstem spreading depolarization may play a pivotal role, as suggested by animal studies. However, patiotemporal details of spreading depolarization occurring in relation to fatal seizures have not been investigated. In addition, little is known about behavioural and neurophysiological features that may discriminate spontaneous fatal from non-fatal seizures. Transgenic mice carrying the missense mutation S218L in the α1A subunit of Cav2.1 (P/Q-type) Ca2+ channels exhibit enhanced excitatory neurotransmission and increased susceptibility to spreading depolarization. Homozygous Cacna1aS218L mice show spontaneous non-fatal and fatal seizures, occurring throughout life, resulting in reduced life expectancy. To identify characteristics of fatal and non-fatal spontaneous seizures, we compared behavioural and electrophysiological seizure dynamics in freely-behaving homozygous Cacna1aS218L mice. To gain insight on the role of brainstem spreading depolarization in SUDEP, we studied the spatiotemporal distribution of spreading depolarization in the context of seizure-related death. Spontaneous and electrically-induced seizures were investigated by video monitoring and electrophysiological recordings in freely-behaving Cacna1aS218L and wild-type mice. Homozygous Cacna1aS218L mice showed multiple spontaneous tonic-clonic seizures and died from SUDEP in adulthood. Death was preceded by a tonic-clonic seizure terminating with hindlimb clonus, with suppression of cortical neuronal activity during and after the seizure. Induced seizures in freely-behaving homozygous Cacna1aS218L mice were followed by multiple spreading depolarizations and death. In wild-type or heterozygous Cacna1aS218L mice, induced seizures and spreading depolarization were never followed by death. To identify temporal and regional features of seizure-induced spreading depolarization related to fatal outcome, diffusion-weighted MRI was performed in anaesthetized homozygous Cacna1aS218L and wild-type mice. In homozygous Cacna1aS218L mice, appearance of seizure-related spreading depolarization in the brainstem correlated with respiratory arrest that was followed by cardiac arrest and death. Recordings in freely-behaving homozygous Cacna1aS218L mice confirmed brainstem spreading depolarization during spontaneous fatal seizures. These data underscore the value of the homozygous Cacna1aS218L mouse model for identifying discriminative features of fatal compared to non-fatal seizures, and support a key role for cortical neuronal suppression and brainstem spreading depolarization in SUDEP pathophysiology. |
| Databáze: | OpenAIRE |
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