Apnea Associated with Brainstem Seizures inCacna1a^S218LMice Is Caused by Medullary Spreading Depolarization

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 Ca V 2.1 Ca 2ϩ 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 nonfatal 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 rostrocaudal direction, preceding local tissue hypoxia and apnea, indicating that invasion of SD into medullary respiratory centers initiated apnea and hypoxia rather than vice versa. Fatal outcome was prevented by timely resuscitation. Moreover, NMDA receptor antagonists MK-801 and memantine prevented seizurerelated 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.

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 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). Cacna1a S218L mice displayed lethal and nonlethal spontaneous seizures.…”

“…These findings, along with previous findings reported by this research group (Loonen et al, 2019), indicate that the Cacna1a S218L mouse might be a useful model to study the mechanisms underlying SUDEP and that brainstem SD is a key feature for the cardiorespiratory dysfunction associated with lethal seizures in this model. Jansen et al (2019) also performed experiments to determine a causal relationship between brainstem SD and brainstem hypoxia. Because hypoxia can promote an SD-like event called anoxic depolarization (Ayata and Lauritzen, 2015), the authors wanted to ensure that SD is a cause and not a consequence of hypoxia during seizures.…”

“…Finally, because the excitatory amino acid glutamate and its NMDA receptors are importantly implicated in the generation and propagation of SD (Ayata and Lauritzen, 2015), Jansen et al (2019) tested whether NMDA receptor antagonism could prevent seizure-related deaths. The authors found that pharmacological interventions with NMDA receptor antagonists (MK-801 or memantine hydrochloride) administered intraperitoneally 30 min before IC stimulation prevented fatal outcomes in all cases and prevented brainstem SD in all except one case (one of eight animals treated with memantine hydrochloride).…”

“…In this regard, it has been suggested that abnormal brainstem serotonergic function could play an important role in SUDEP by impairing CO 2 -induced arousal during ictal and postictal periods (Zhan et al, 2016;Smith et al, 2018), likely aggravating apnea, hypoxia, and acidosis. Thus, it is plausible that the brainstem SD observed in Cacna1a S218L mice (Jansen et al, 2019) and other SUDEP mouse models (Aiba and Noebels, 2015) depresses the activity of DRN serotonergic neurons, impairing CO 2 -induced arousal from sleep, and, ultimately, contribute to fatal outcomes by worsening apnea, hypoxia, and acidosis during seizures.…”