Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy
Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy
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DOI：
10.1093/brain/awq057
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发表时间：
2010-05-01
期刊：
影响因子：
14.5
通讯作者：
Lerche, Holger
中科院分区：
文献类型：
--
作者：
Liao, Yunxiang;Deprez, Liesbet;Lerche, Holger
许多特发性癫痫综合征具有特征性的年龄依赖性，其潜在的分子机制在很大程度上是未知的。在这里，我们提出了一个机制，可以解释，癫痫发作在良性家族性脑-婴儿癫痫发作几乎完全发生在生命的第一天到几个月。良性家族性癫痫发作是由编码电压门控Na（+）通道Na（V）1.2的基因SCN 2A突变引起的。我们确定了两个新的SCN 2A突变引起良性家族性脑-婴儿癫痫发作，并分析了这些突变在新生儿和成人剪接变异体的人Na（+）通道Na（V）1.2的功能后果在tsA 201细胞中异源表达与β 1和β 2亚基。我们发现显著的门控变化导致功能获得，例如持续Na（+）电流增加，快速失活的加速恢复或稳态激活的电压依赖性改变。这些仅限于新生儿剪接变异的一个突变，但更明显的成人形式的其他，这表明差异发育剪接并不能提供一个一般性的解释癫痫缓解。因此，我们在小鼠脑切片中使用免疫组织化学和实时逆转录聚合酶链反应分析了Na（V）1.2和另一种电压门控Na（+）通道Na（V）1.6的发育表达。我们发现Na（V）1.2通道在海马和皮质中主要神经元的轴突起始段的发育早期表达，但其表达减少，并且在成熟过程中逐渐被Na（V）1.6取代为主导通道类型。这一发现为突变型Na（V）1.2通道功能获得性发作的瞬时表达提供了合理的解释。
Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infantile seizures are caused by mutations in the gene SCN2A encoding the voltage-gated Na(+) channel Na(V)1.2. We identified two novel SCN2A mutations causing benign familial neonatal-infantile seizures and analysed the functional consequences of these mutations in a neonatal and an adult splice variant of the human Na(+) channel Na(V)1.2 expressed heterologously in tsA201 cells together with beta1 and beta2 subunits. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na(+) current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced for the adult form for the other, suggesting that a differential developmental splicing does not provide a general explanation for seizure remission. We therefore analysed the developmental expression of Na(V)1.2 and of another voltage-gated Na(+) channel, Na(V)1.6, using immunohistochemistry and real-time reverse transcription-polymerase chain reaction in mouse brain slices. We found that Na(V)1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by Na(V)1.6 during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant Na(V)1.2 channels.