γ-Aminobutyric acid receptor alpha 1 subunit loss of function causes genetic generalized epilepsy by impairing inhibitory network neurodevelopment
γ-Aminobutyric acid receptor alpha 1 subunit loss of function causes genetic generalized epilepsy by impairing inhibitory network neurodevelopment
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DOI：
10.1111/epi.14576
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发表时间：
2018-11-01
期刊：
影响因子：
5.6
通讯作者：
Drapeau, Pierre
中科院分区：
文献类型：
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作者：
Samarut, Eric;Swaminathan, Amrutha;Drapeau, Pierre
目的γ-氨基丁酸受体亚单位1（GABRA 1）基因突变可引起人类轻、重度全身性癫痫。虽然这些致癫痫突变已被证明在体外破坏受体活性，但其对大脑发育和活动的体内后果尚不清楚。在这里，我们的目的是解开癫痫的GABRA 1功能丧失的机制。方法结果我们产生了一个gabra 1（-/-）斑马鱼突变株，表现出高度渗透性癫痫发作。我们试图通过对gabra 1（-/-）幼虫脑的无偏全转录组分析来确定潜在的分子机制。有趣的是，突变鱼在幼年阶段显示完全渗透性癫痫发作，准确地模仿在患者中观察到的强直阵挛性全身性癫痫发作。此外，高渗透性癫痫发作可以通过光刺激诱导，从而为我们提供了第一个斑马鱼模型，其中明显的癫痫发作可以由非化学试剂诱导。我们的转录组学分析确定了正确的大脑发育所必需的几个途径中的失调基因。更具体地说，我们表明，大脑抑制网络的早期发展受到特别影响。虽然GABA能神经元的数量没有改变，但我们观察到抑制性突触的数量急剧减少，GABA能网络的复杂性降低。这与参与轴突引导和突触形成的许多基因表达的中断是一致的。与GABA在神经发育中的作用一起，我们的数据确定了癫痫发生的一个新方面，表明GABRA 1缺乏性癫痫的基础是早期脑神经发育缺陷的结果，特别是在抑制性网络布线水平。
Objective In humans, mutations of the gamma-aminobutyric acid receptor subunit 1 (GABRA1) cause either mild or severe generalized epilepsy. Although these epilepsy-causing mutations have been shown to disrupt the receptor activity in vitro, their in vivo consequences on brain development and activity are not known. Here, we aim at unraveling the epileptogenesis mechanisms of GABRA1 loss of function. Methods Results We generated a gabra1(-/-) zebrafish mutant line displaying highly penetrant epileptic seizures. We sought to identify the underlying molecular mechanisms through unbiased whole transcriptomic assay of gabra1(-/-) larval brains. Interestingly, mutant fish show fully penetrant seizures at juvenile stages that accurately mimic tonic-clonic generalized seizures observed in patients. Moreover, highly penetrant seizures can be induced by light stimulation, thus providing us with the first zebrafish model in which evident epileptic seizures can be induced by nonchemical agents. Our transcriptomic assay identified misregulated genes in several pathways essential for correct brain development. More specifically, we show that the early development of the brain inhibitory network is specifically affected. Although the number of GABAergic neurons is not altered, we observed a drastic reduction in the number of inhibitory synapses and a decreased complexity of the GABAergic network. This is consistent with the disruption in expression of many genes involved in axon guidance and synapse formation. Significance Together with the role of GABA in neurodevelopment, our data identify a novel aspect of epileptogenesis, suggesting that the substratum of GABRA1-deficiency epilepsy is a consequence of early brain neurodevelopmental defects, in particular at the level of inhibitory network wiring.