Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy.
Adrenergic Mechanisms of Audiogenic Seizure-Induced Death in a Mouse Model of SCN8A Encephalopathy.
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DOI：
10.3389/fnins.2021.581048
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发表时间：
2021
影响因子：
4.3
通讯作者：
Patel MK
中科院分区：
文献类型：
--
作者：
Wengert ER;Wenker IC;Wagner EL;Wagley PK;Gaykema RP;Shin JB;Patel MK
癫痫猝死（SUDEP）是当前治疗方法不能充分控制癫痫发作的患者死亡的主要原因。SCN8A脑病患者发生SUDEP的风险增高。虽然转基因小鼠模型已经提供了对SCN8A脑病病因的分子机制的深入了解，但我们对癫痫性死亡的理解一直受到无法可靠地触发这些小鼠癫痫发作和癫痫性死亡的阻碍。在这里，我们证明了携带Scn8a等位基因的小鼠具有患者来源的突变N1768D (D/+)，容易发生听源性癫痫发作和癫痫引起的死亡。在成年D/+小鼠中，听源性癫痫发作是非致命性的，并且与自发性癫痫发作具有几乎相同的行为、电图和心肺特征。相反，在出生后20-21天，D/+小鼠表现出相同的癫痫行为，但在听源性癫痫发作后癫痫致死亡的发生率明显更高。通过机械通气刺激呼吸或肾上腺素能受体的急性激活来预防癫痫引起的死亡。相反，在成年D/+小鼠中，肾上腺素能受体的抑制使正常情况下非致死性听源性癫痫发作转变为致死性癫痫发作。综上所述，我们的研究表明，在我们的新型听源性癫痫性死亡模型中，肾上腺素能受体的激活对于恢复呼吸和预防癫痫性死亡是必要和充分的。
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death amongst patients whose seizures are not adequately controlled by current therapies. Patients with SCN8A encephalopathy have an elevated risk for SUDEP. While transgenic mouse models have provided insight into the molecular mechanisms of SCN8A encephalopathy etiology, our understanding of seizure-induced death has been hampered by the inability to reliably trigger both seizures and seizure-induced death in these mice. Here, we demonstrate that mice harboring an Scn8a allele with the patient-derived mutation N1768D (D/+) are susceptible to audiogenic seizures and seizure-induced death. In adult D/+ mice, audiogenic seizures are non-fatal and have nearly identical behavioral, electrographical, and cardiorespiratory characteristics as spontaneous seizures. In contrast, at postnatal days 20–21, D/+ mice exhibit the same seizure behavior, but have a significantly higher incidence of seizure-induced death following an audiogenic seizure. Seizure-induced death was prevented by either stimulating breathing via mechanical ventilation or by acute activation of adrenergic receptors. Conversely, in adult D/+ mice inhibition of adrenergic receptors converted normally non-fatal audiogenic seizures into fatal seizures. Taken together, our studies show that in our novel audiogenic seizure-induced death model adrenergic receptor activation is necessary and sufficient for recovery of breathing and prevention of seizure-induced death.
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影响因子：
3.4
作者：
Fleming SM;Jordan MC;Mulligan CK;Masliah E;Holden JG;Millard RW;Chesselet MF;Roos KP
通讯作者：
Roos KP
影响因子：
3.7
作者：
Auerbach DS;Jones J;Clawson BC;Offord J;Lenk GM;Ogiwara I;Yamakawa K;Meisler MH;Parent JM;Isom LL
通讯作者：
Isom LL
影响因子：
2.2
作者：
Faingold, Carl L.;Randall, Marc;Kommajosyula, Srinivasa P.
通讯作者：
Kommajosyula, Srinivasa P.
羟色胺神经元具有抗惊厥作用，可降低癫痫发作引起的死亡率
影响因子：
5.5
作者：
Buchanan, Gordon F.;Murray, Nicholas M.;Richerson, George B.
通讯作者：
Richerson, George B.
影响因子：
5.6
作者：
Baker EM;Thompson CH;Hawkins NA;Wagnon JL;Wengert ER;Patel MK;George AL Jr;Meisler MH;Kearney JA
通讯作者：
Kearney JA