Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations
Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations
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DOI：
10.1093/cercor/bhu090
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发表时间：
2015-09-01
期刊：
影响因子：
3.7
通讯作者：
Marsh, Eric D.
中科院分区：
文献类型：
--
作者：
Simonet, Jacqueline C.;Sunnen, C. Nicole;Marsh, Eric D.
Aristaless 相关同源框 (ARX) 基因的突变会导致儿童大脑结构异常、癫痫和神经认知缺陷。在前脑发育过程中，Arx 在大脑皮层和大脑皮层下祖细胞中表达。我们之前证明，从皮层下衍生的皮质中间神经元中消除 Arx 会产生癫痫表型，其特征与 ARX 突变患者中所见的特征重叠。在本报告中，我们选择性地从产生大脑皮层投射神经元的大脑皮层祖细胞中去除了 Arx。虽然没有记录到明显的癫痫发作活动，但这些小鼠表现出了一系列特殊的行为。与野生型同窝动物相比，它们不那么焦虑，不那么社交，而且更活跃。整体皮质厚度减少，胼胝体和前连合发育不全，这与皮质连接的扰动一致。总而言之，这些数据表明，ARX 突变患者中常见的一些结构和行为异常具体是由于大脑皮层祖细胞功能的改变所致。此外，我们的数据表明，在 ARX 突变患者中发现的一些神经行为特征可能不是由持续的癫痫发作引起的，正如人们通常假设的那样，因为在这些行为分析中癫痫作为一个混杂变量被消除了。
Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses.