Brainstem spreading depolarization and cortical dynamics during fatal seizures inCacna1aS218L 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 a 1A subunit of Ca v 2.1 (P/Q-type) Ca 2+ 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.

Analysis of gene variants in the GASH/Sal model of epilepsy

“…Cacna1a S218L mice contain the missense mutation S218L in the alpha1a subunit of CaV2.1 voltage-gated Ca2+ channels and show increased excitatory neurotransmission and susceptibility to spreading depolarization. In addition, Cacna1a S218L mice homozygous for the mutation develop multiple, spontaneous, tonic clonic seizures and die from sudden unexpected death in epilepsy (SUDEP) [48]. Recently, Jiang and colleagues [49], have demonstrated that both gain-and loss-of-function Cacna1a mutations are associated with developmental epileptic encephalopathies.…”

Cardiorespiratory Dysfunction Induced by Brainstem Spreading Depolarization: A Potential Mechanism for SUDEP

“…A recent study published in The Journal of Neuroscience by Jansen et al (2019) provides new insights into the potential mechanisms underlying SUDEP. The authors used a transgenic mouse model (Cacna1a S218L mice) carrying a homozygous S218L missense mutation that leads to gain of function of voltage-gated CaV2.1 Ca 2ϩ channels and increased risk for spontaneous fatal seizures, and which has been proposed as a SUDEP model (Loonen et al, 2019). The main finding of Jansen et al (2019) was that that cardiorespiratory dysfunction related to spontaneous brainstem seizures in Cacna1a S218L mice is caused by medullary spreading depolarization (SD).…”

Adenosine kinase and adenosine receptors A1R and A2AR in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP

“…Of interest, tolerance to hypoxia is mediated through A 1 R, 46 and patients with apnea undergoing amygdala stimulation had no symptoms of dyspnea, 45 which could be an adenosine‐mediated effect. Furthermore, evidence supports brainstem spreading depolarization as a final postictal event in SUDEP 47 ; in the CACNA1A model of SUDEP, spreading depolarization extended through subcortical regions and the amygdala before brainstem extension 48 . There is evidence that adenosine may be responsible for prolonged depression of synaptic transmission after spreading depolarization via A 1 R receptor activation 49 .…”