Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice

Abstract

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 α_1A subunit of Ca_v2.1 (P/Q-type) Ca²⁺ channels exhibit enhanced excitatory neurotransmission and increased susceptibility to spreading depolarization. Homozygous Cacna1a^S218L 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 Cacna1a^S218L 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 Cacna1a^S218L and wild-type mice. Homozygous Cacna1a^S218L 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 Cacna1a^S218L mice were followed by multiple spreading depolarizations and death. In wild-type or heterozygous Cacna1a^S218L 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 Cacna1a^S218L and wild-type mice. In homozygous Cacna1a^S218L 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 Cacna1a^S218L mice confirmed brainstem spreading depolarization during spontaneous fatal seizures. These data underscore the value of the homozygous Cacna1a^S218L 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.

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