Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms.
Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms.
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DOI：
10.1016/j.expneurol.2020.113388
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发表时间：
2020-10
影响因子：
5.3
通讯作者：
Coulter DA
中科院分区：
文献类型：
--
作者：
Mulcahey PJ;Tang S;Takano H;White A;Davila Portillo DR;Kane OM;Marsh ED;Zhou Z;Coulter DA
CDKL5缺乏症（CDD）是一种以早发性癫痫、严重智力残疾、皮质性视觉障碍和运动障碍为特征的毁灭性神经发育障碍。癫痫是CDD的中心特征，大多数患者具有顽固性癫痫发作，但癫痫发作频率和严重程度可能不同。临床报告表明，癫痫发作的症状和电图特征的多样性，没有CDD的模式诊断。虽然CDD的动物模型已经显示出过度兴奋的证据，自发性癫痫发作以前没有报道。在这里，我们提出了第一个系统的研究自发性癫痫发作的小鼠模型的CDD。癫痫痉挛是CDD患者中最常见和最持久的癫痫发作类型，在携带杂合突变Cdkl5R59X和Cdkl5KO的两种CDD小鼠模型中重现。痉挛样事件存在于携带两种Cdkl5突变中的任一种的老年杂合雌性小鼠中的显著比例中，其癫痫发作负荷具有显著变化。从心电图上看，痉挛最常与全身慢波活动相关，并倾向于在睡眠期间成群发生。CDD小鼠还表现出发作间期和背景异常，其特征在于高振幅尖峰和多个频带中的功率改变。这些数据表明，老年雌性杂合Cdkl5小鼠概括了CDD癫痫的多种特征，并可在未来的机制和转化研究中补充现有的癫痫痉挛模型。
CDKL5 deficiency disorder (CDD) is a devastating neurodevelopmental disorder characterized by early-onset epilepsy, severe intellectual disability, cortical visual impairment and motor disabilities. Epilepsy is a central feature of CDD, with most patients having intractable seizures, but seizure frequency and severity can vary. Clinical reports demonstrate a diversity in seizure semiology and electrographic features, with no pattern diagnostic of CDD. Although animal models of CDD have shown evidence of hyperexcitability, spontaneous seizures have not been previously reported. Here, we present the first systematic study of spontaneous seizures in mouse models of CDD. Epileptic spasms, the most frequent and persistent seizure type in CDD patients, were recapitulated in two mouse models of CDD carrying heterozygous mutations, Cdkl5R59X and Cdkl5KO. Spasm-like events were present in a significant proportion of aged heterozygous female mice carrying either of the two Cdkl5 mutations with significant variability in seizure burden. Electrographically, spasms were most frequently associated with generalized slow-wave activity and tended to occur in clusters during sleep. CDD mice also showed interictal and background abnormalities, characterized by high-amplitude spiking and altered power in multiple frequency bands. These data demonstrate that aged female heterozygous Cdkl5 mice recapitulate multiple features of epilepsy in CDD and can serve to complement existing models of epileptic spasms in future mechanistic and translational studies.
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