An Epilepsy-Related ARX Polyalanine Expansion Modifies Glutamatergic Neurons Excitability and Morphology Without Affecting GABAergic Neurons Development
An Epilepsy-Related ARX Polyalanine Expansion Modifies Glutamatergic Neurons Excitability and Morphology Without Affecting GABAergic Neurons Development
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DOI：
10.1093/cercor/bhs138
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发表时间：
2013-06-01
期刊：
影响因子：
3.7
通讯作者：
Represa, Alfonso
中科院分区：
文献类型：
--
作者：
Beguin, Shirley;Crepel, Valerie;Represa, Alfonso
癫痫性脑病包括一组异质性的严重婴儿疾病，其中癫痫的病理生理基础是不准确的阐明基因型表型分析。由于在这些综合征中发现了GABA神经元的缺陷，特别是在伴有生殖器异常的x连锁无脑畸形患者中，癫痫被认为是由GABA能抑制的不平衡引起的，并提出了神经间病变的概念。在这里，我们研究了马兜铃相关同源盒（ARX）基因的聚丙氨酸扩增的影响，这是一种在West综合征和Ohtahara综合征中发现的突变。对Arx（(GCG)7/Y）敲入小鼠的分析显示，GABA神经元的发育不受影响。此外，锥体细胞迁移和皮层分层在这些小鼠中没有改变。有趣的是，电生理记录显示海马锥体神经元显示出与野生型（WT）小鼠相似的抑制性突触后电流频率。然而，这些神经元表现出与轴突树化重构相关的兴奋性输入频率的急剧增加，这表明Arx（(GCG)7/Y）小鼠的癫痫可能是由谷氨酸网络重构引起的。因此，我们提出继发性改变有助于疾病特异性表型的发展，并应考虑解释与癫痫突变相关的表型多样性。
Epileptic encephalopathies comprise a heterogeneous group of severe infantile disorders for which the pathophysiological basis of epilepsy is inaccurately clarified by genotypephenotype analysis. Because a deficit of GABA neurons has been found in some of these syndromes, notably in patients with X-linked lissencephaly with abnormal genitalia, epilepsy was suggested to result from an imbalance in GABAergic inhibition, and the notion of interneuronopathy was proposed. Here, we studied the impact of a polyalanine expansion of aristaless-related homeobox (ARX) gene, a mutation notably found in West and Ohtahara syndromes. Analysis of Arx((GCG)7/Y) knock-in mice revealed that GABA neuron development is not affected. Moreover, pyramidal cell migration and cortical layering are unaltered in these mice. Interestingly, electrophysiological recordings show that hippocampal pyramidal neurons displayed a frequency of inhibitory postsynaptic currents similar to wild-type (WT) mice. However, these neurons show a dramatic increase in the frequency of excitatory inputs associated with a remodeling of their axonal arborization, suggesting that epilepsy in Arx((GCG)7/Y)mice would result from a glutamate network remodeling. We therefore propose that secondary alterations are instrumental for the development of disease-specific phenotypes and should be considered to explain the phenotypic diversity associated with epileptogenic mutations.