Hyperexcitable superior colliculus and fatal brainstem spreading depolarization in a model of Sudden Unexpected Death in Epilepsy

Abstract

Cardiorespiratory arrest and death in mouse models of Sudden Unexpected Death in Epilepsy occur when spreading depolarization is triggered by cortical seizures and then propagates to the brainstem. However, the critical brain regions and the specific changes required to allow spreading depolarization to propagate to the brainstem under the relatively rare circumstances leading to a fatal seizure are unknown. We previously found that following cortical seizure-inducing electrical stimulation, spreading depolarization could occur in both the superior and inferior colliculi in Cacna1aS218L mice, but was never observed in wild-type animals or following non-seizure-inducing stimuli in Cacna1aS218L mice. Here, we show that optogenetic stimulation of the superior/inferior colliculi in Cacna1aS218L mice induces severe seizures, and resulting spreading depolarization in the superior/inferior colliculi that propagates to the brainstem and correlates with respiratory arrest followed by cardiac arrest. Further, we show that neurons of the superior colliculus in Cacna1aS218L mice exhibit hyperexcitable properties that we propose underlie a distinct susceptibility to spreading depolarization. Our data suggest that the susceptibility of the superior colliculus to elicit fatal spreading depolarization is a result of either genetic or seizure-related alterations within the superior colliculus that may involve changes to structure, connectivity and/or excitability.

Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

“…Brainstem spreading depolarization (SD) has been reported to be associated with SUDEP pathophysiology in some transgenic mouse models using anesthetic preparations (Aiba and Noebels, 2015; Aiba et al, 2016; Cain et al, 2022). Further, several rodent studies using general anesthesia have reported an association between brain hypoxia and SD (Funke et al, 2009; Richter et al, 2010).…”

“…Aiba and Noebels, 2015;Aiba et al, 2016;Cain et al, 2022). Further, several rodent studies using general anesthesia have reported an association between brain hypoxia and SD(Funke et al, 2009;Richter et al, 2010).…”

Sudden unexpected death in epilepsy

“…It has long been known to underlie pathophysiology in migraine and has more recently been implicated in traumatic brain injury, epilepsy and SUDEP [81]. Recent studies in a hyperexcitable mouse model demonstrate that when SD reaches superior colliculus, it is more likely to be fatal [86,87 ▪ ,88]. In certain syndromic epilepsies, ion channel mutations could also be present in key control regions and directly impair cardiorespiratory function in this manner [49].…”

Perspectives on the basis of seizure-induced respiratory dysfunction

“…Similar results were also observed in mice expressing a Ca v 2.1 gain of function mutation associated with familial hemiplegic migraine type 1 10.3389/fncir.2022.1033756 (Cacna1a S218L/+ ; Jansen et al, 2019) and mice expressing a ryanodine receptor-2 gain of function mutation associated with catecholaminergic polymorphic ventricular tachycardia (Aiba et al, 2016). Also, in Cacna1a S218L/+ mice the superior colliculus, a midbrain structure that receives input from both the cortex and brainstem, was particularly effective at propagating seizureinduced SD to the brainstem (Cain et al, 2022), suggesting anatomical connectivity may facilitate SD.…”