Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON, Canada N6A 5C1.
Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada N6A 5C1.
Dis Model Mech. 2021 Jan 26;14(1):dmm046235. doi: 10.1242/dmm.046235.
Connexin 30 (Cx30; also known as when referring to the mouse gene) is expressed in ependymal cells of the brain ventricles, in leptomeningeal cells and in astrocytes rich in connexin 43 (Cx43), leading us to question whether patients harboring mutations exhibit any brain anomalies. Here, we used mice harboring the human disease-associated A88V Cx30 mutation to address this gap in knowledge. Brain Cx30 levels were lower in male and female Cx30 mice compared with Cx30 and Cx30 mice, whereas Cx43 levels were lower only in female Cx30 mutant mice. Characterization of brain morphology revealed a disrupted ependymal cell layer, significant hydrocephalus and enlarged ventricles in 3- to 6-month-old adult male and female Cx30 mice compared with Cx30 or Cx30 sex-matched littermate mice. To determine the functional significance of these molecular and morphological changes, we investigated a number of behavioral activities in these mice. Interestingly, only female Cx30 mice exhibited abnormal behavior compared with all other groups. Cx30 female mice demonstrated increased locomotor and exploratory activity in both the open field and the elevated plus maze. They also exhibited dramatically reduced ability to learn the location of the escape platform during Morris water maze training, although they were able to swim as well as other genotypes. Our findings suggest that the homozygous A88V mutation in Cx30 causes major morphological changes in the brain of aging mice, possibly attributable to an abnormal ependymal cell layer. Remarkably, these changes had a more pronounced consequence for cognitive function in female mice, which is likely to be linked to the dysregulation of both Cx30 and Cx43 levels in the brain.
连接蛋白 30（Cx30；在提到小鼠基因时也称为 ）在脑室内的室管膜细胞、软脑膜细胞和富含连接蛋白 43（Cx43）的星形胶质细胞中表达，这使我们质疑是否携带 突变的患者存在任何脑异常。在这里，我们使用携带与人相关疾病相关的 A88V Cx30 突变的小鼠来解决这一知识空白。与 Cx30 和 Cx30 小鼠相比，雄性和雌性 Cx30 小鼠的脑 Cx30 水平较低，而只有雌性 Cx30 突变小鼠的 Cx43 水平较低。脑形态特征表明，与 Cx30 或 Cx30 性别匹配的同窝仔鼠相比，3 至 6 个月大的成年雄性和雌性 Cx30 小鼠的室管膜细胞层被破坏，出现明显的脑积水和脑室扩大。为了确定这些分子和形态变化的功能意义，我们在这些小鼠中研究了一些行为活动。有趣的是，只有雌性 Cx30 小鼠与所有其他组相比表现出异常行为。与其他所有组相比，Cx30 雌性小鼠在开阔场和高架十字迷宫中表现出更高的运动和探索活性。它们在莫里斯水迷宫训练中也表现出明显降低的逃避平台位置学习能力，尽管它们的游泳能力与其他基因型一样。我们的研究结果表明，Cx30 中的纯合 A88V 突变导致老年小鼠大脑发生重大形态变化，这可能归因于异常的室管膜细胞层。值得注意的是，这些变化对雌性小鼠的认知功能产生了更明显的影响，这可能与大脑中 Cx30 和 Cx43 水平的失调有关。
