Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy
Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy
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DOI：
10.1073/pnas.0813330106
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发表时间：
2009-03-10
影响因子：
11.1
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
Oakley, John C.;Kalume, Franck;Catterall, William A.
I 型电压门控钠通道 Na(V)1.1 α 亚基的杂合功能丧失突变可导致婴儿期严重肌阵挛癫痫 (SMEI)，这是一种婴儿期发病的癫痫性脑病，其特征是正常发育，随后出现治疗难治性热性和非热性惊厥以及精神运动性衰退。由 Na(V)1.1 通道杂合缺失产生的 SMEI (mSMEI) 小鼠会出现癫痫发作和共济失调。在这里，我们研究了 mSMEI 中癫痫发作和发作间期癫痫样棘波活动的温度和年龄依赖性。视频-脑电图联合监测表明，mSMEI 因身体核心温度升高而诱发癫痫发作，但野生型小鼠不受影响。在测试的 3 个年龄组中，出生后 (P) 17-18 mSMEI 没有出现温度诱发的癫痫发作，但几乎所有 P20-22 和 P30-46 mSMEI 均出现肌阵挛癫痫发作，随后是核心体温升高引起的全身性癫痫发作。仅在 P32 龄以上的小鼠中观察到自发性癫痫发作，这表明 mSMEI 在自发性癫痫发作之前变得容易受到温度诱导的癫痫发作的影响。大多数 P30-46 mSMEI 在正常体温下观察到发作间期尖峰活动，但在 P20-22 或 P17-18 mSMEI 中未观察到，表明发作间期癫痫活动与癫痫发作易感性相关。大多数 P20-22 mSMEI 具有发作间期尖峰活动并伴有体温升高。我们的结果定义了 SMEI 对癫痫发作易感性的关键发育转变，证明仅体温升高就足以诱发癫痫发作，并揭示了人和小鼠 SMEI 在癫痫发作频率和严重程度的惊人温度和年龄依赖性以及发作间期癫痫样尖峰活动的温度依赖性和频率方面存在密切对应关系。
Heterozygous loss-of-function mutations in the alpha subunit of the type I voltage-gated sodium channel Na(V)1.1 cause severe myoclonic epilepsy in infancy (SMEI), an infantile-onset epileptic encephalopathy characterized by normal development followed by treatment-refractory febrile and afebrile seizures and psychomotor decline. Mice with SMEI (mSMEI), created by heterozygous deletion of Na(V)1.1 channels, develop seizures and ataxia. Here we investigated the temperature and age dependence of seizures and interictal epileptiform spike-and-wave activity in mSMEI. Combined video-EEG monitoring demonstrated that mSMEI had seizures induced by elevated body core temperature but wild-type mice were unaffected. In the 3 age groups tested, no postnatal day (P) 17-18 mSMEI had temperature-induced seizures, but nearly all P20-22 and P30-46 mSMEI had myoclonic seizures followed by generalized seizures caused by elevated core body temperature. Spontaneous seizures were only observed in mice older than P32, suggesting that mSMEI become susceptible to temperature-induced seizures before spontaneous seizures. Interictal spike activity was seen at normal body temperature in most P30-46 mSMEI but not in P20-22 or P17-18 mSMEI, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20-22 mSMEI had interictal spike activity with elevated body temperature. Our results define a critical developmental transition for susceptibility to seizures in SMEI, demonstrate that body temperature elevation alone is sufficient to induce seizures, and reveal a close correspondence between human and mouse SMEI in the striking temperature and age dependence of seizure frequency and severity and in the temperature dependence and frequency of interictal epileptiform spike activity.