Defective Excitatory/Inhibitory Synaptic Balance and Increased Neuron Apoptosis in a Zebrafish Model of Dravet Syndrome
Defective Excitatory/Inhibitory Synaptic Balance and Increased Neuron Apoptosis in a Zebrafish Model of Dravet Syndrome
复制标题
斑马鱼德雷维综合征模型中的兴奋/抑制突触平衡缺陷和神经元凋亡增加
DOI：
10.3390/cells8101199
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发表时间：
2019-10-01
期刊：
影响因子：
6
通讯作者：
Soussi-Yanicostas, Nadia
中科院分区：
文献类型：
--
作者：
Brenet, Alexandre;Hassan-Abdi, Rahma;Soussi-Yanicostas, Nadia
Dravet综合征是一种严重的儿童癫痫，对目前的抗癫痫药物反应不佳。近年来，人们建立了Scn1Lab钠通道缺陷的斑马鱼疾病模型，以寻找新的抗癫痫药物候选物，其中一些目前正在进行临床试验。然而，在斑马鱼幼体中观察到的Scn1Lab耗竭后神经元缺陷的光谱尚未完全探索。为了填补这一空白，并获得一个更好的理解的机制，神经元过度兴奋的Scn1Lab耗尽的幼虫，我们分析了在体内神经元的活动，结合局部场电位记录和瞬时钙摄取成像，研究兴奋性和抑制性突触和神经元的分布，以及调查神经元凋亡。我们发现，Scn1Lab耗尽的幼虫显示复发性癫痫样发作事件，与大量的同步钙摄取和发作样局部场电位爆发。Scn1Lab耗竭还导致神经元和突触平衡向兴奋和增加神经元死亡的戏剧性转变。因此，我们的研究结果提供了在体内的证据表明，Scn1Lab功能丧失导致神经元过度兴奋的结果，突触平衡紊乱和神经元凋亡增加。
Dravet syndrome is a type of severe childhood epilepsy that responds poorly to current anti-epileptic drugs. In recent years, zebrafish disease models with Scn1Lab sodium channel deficiency have been generated to seek novel anti-epileptic drug candidates, some of which are currently undergoing clinical trials. However, the spectrum of neuronal deficits observed following Scn1Lab depletion in zebrafish larvae has not yet been fully explored. To fill this gap and gain a better understanding of the mechanisms underlying neuron hyperexcitation in Scn1Lab-depleted larvae, we analyzed neuron activity in vivo using combined local field potential recording and transient calcium uptake imaging, studied the distribution of excitatory and inhibitory synapses and neurons as well as investigated neuron apoptosis. We found that Scn1Lab-depleted larvae displayed recurrent epileptiform seizure events, associating massive synchronous calcium uptakes and ictal-like local field potential bursts. Scn1Lab-depletion also caused a dramatic shift in the neuronal and synaptic balance toward excitation and increased neuronal death. Our results thus provide in vivo evidence suggesting that Scn1Lab loss of function causes neuron hyperexcitation as the result of disturbed synaptic balance and increased neuronal apoptosis.