Impaired Action Potential Initiation in GABAergic Interneurons Causes Hyperexcitable Networks in an Epileptic Mouse Model Carrying a Human NaV1.1 Mutation
Impaired Action Potential Initiation in GABAergic Interneurons Causes Hyperexcitable Networks in an Epileptic Mouse Model Carrying a Human NaV1.1 Mutation
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DOI：
10.1523/jneurosci.0721-14.2014
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发表时间：
2014-11-05
影响因子：
5.3
通讯作者：
Lerche, Holger
中科院分区：
文献类型：
--
作者：
Hedrich, Ulrike B. S.;Liautard, Camille;Lerche, Holger
SCN 1A和其他离子通道基因的突变可以导致不同的癫痫表型，但过度兴奋网络发展的确切机制在很大程度上是未知的。在这里，我们提出了一个多系统分析的SCN 1A小鼠模型携带Na（V）1.1-R1648 H突变，导致热性惊厥和癫痫的人。我们发现丘脑、皮质和海马的中间神经元普遍存在低兴奋性，而兴奋性神经元没有可检测到的变化。有趣的是，中间神经元的体细胞Na+通道和持续性Na+电流没有显着变化。相反，中间神经元功能障碍的关键机制是通过分析动作电位放电确定的轴突起始段的动作电位起始缺陷。这种赤字增加与射击期间的持续时间，这表明增加缓慢失活，记录重组突变的通道，可以发挥重要作用。中间神经元放电的缺陷导致兴奋性神经元的动作电位驱动抑制减少，这一点由不太频繁的自发性IPSC而非微型IPSC所揭示。多种方法表明突变小鼠自发性丘脑皮层和海马网络活动增加，如下：（1）在多电极阵列上的原代神经元培养物中记录到更多的同步和更高频率的放电：（2）场电位记录检查的丘脑皮层切片显示自发活动和病理性高频振荡;（3）海马脑片多神经元Ca ~（2+）显像显示神经元自发活动增强。因此，在动作电位起始中的神经元间特异性的一般性缺陷导致多系统去抑制和网络过度兴奋，这可以很好地解释所研究的小鼠模型和携带这种突变的患者中癫痫发作的发生。
Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the Na(V)1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na+ channels in interneurons and persistent Na+ currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca2+ imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.