Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice
Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1a S218L mice
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DOI：
10.1093/brain/awy325
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发表时间：
2019-02-01
期刊：
影响因子：
14.5
通讯作者：
Tolner, Else A.
中科院分区：
文献类型：
--
作者：
Loonen, Inge C. M.;Jansen, Nico A.;Tolner, Else A.
癫痫猝死（SUDEP）是癫痫的一种致命并发症，脑干扩散性去极化可能在其中起关键作用，动物研究表明。然而，时空细节的扩散去极化发生在致命的癫痫发作尚未调查。此外，很少有人知道的行为和神经生理学特征，可以区分自发性致命的非致命性癫痫发作。在Ca（v）2.1（P/Q型）Ca 2+通道（1A）亚基中携带错义突变S218 L的转基因小鼠表现出增强的兴奋性神经传递和增加的对扩展性去极化的敏感性。纯合子Cacna 1a（S218 L）小鼠表现出自发性非致命性和致命性癫痫发作，终生发生，导致预期寿命缩短。为了确定致命性和非致命性自发性癫痫发作的特征，我们比较了行为自由的纯合子Cacna 1a（S218 L）小鼠的行为和电生理癫痫发作动力学。为了深入了解脑干扩展性去极化在SUDEP中的作用，我们研究了脑干扩展性去极化的时空分布在与死亡相关的背景下。通过视频监测和电生理记录在自由行为的Cacna 1a（S218 L）和野生型小鼠中研究自发和电诱导癫痫发作。纯合子Cacna 1a（S218 L）小鼠表现出多次自发性强直-阵挛性癫痫发作，并在成年期死于SUDEP。死亡之前是强直阵挛性癫痫发作，以后肢阵挛终止，癫痫发作期间和之后皮质神经元活动受到抑制。在行为自由的纯合子Cacna 1a（S218 L）小鼠中诱导癫痫发作，随后出现多次扩散性去极化和死亡。在野生型或杂合型Cacna 1a（S218 L）小鼠中，诱导癫痫发作和扩散性去极化从未导致死亡。为了确定与致死性结局相关的癫痫诱导的扩散性去极化的时间和区域特征，在麻醉的纯合子Cacna 1a（S218 L）和野生型小鼠中进行了弥散加权MRI。在纯合子Cacna 1a（S218 L）小鼠中，脑干中出现与呼吸骤停相关的扩散性去极化，随后发生心脏骤停和死亡。在行为自由的纯合子Cacna 1a（S218 L）小鼠中的记录证实了自发性致命癫痫发作期间脑干扩散去极化。这些数据强调了纯合Cacna 1a（S218 L）小鼠模型用于识别致命性癫痫发作与非致命性癫痫发作的区别特征的价值，并支持皮质神经元抑制和脑干扩散去极化在SUDEP病理生理学中的关键作用。
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 (1A) subunit of Ca(v)2.1 (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.