Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.
Department of Neurology, University of California, San Francisco, San Francisco 94158, CA, United States.
Neuroscience. 2018 Aug 1;384:300-313. doi: 10.1016/j.neuroscience.2018.05.021. Epub 2018 Jun 3.
Several conditions related to the intrauterine environment are associated with neuropsychiatric conditions in later life. In humans, approximately 2% of infants are exposed to perinatal hypoxia-ischemia or prolonged anoxic insult, a condition to which very low birth weight preterm infants exhibit the highest susceptibility. Analyses of postmortem tissue link some presentations of these conditions to changes in GABA pathway functionality in the brains of affected subjects. Using animal models of early-life hypoxia-ischemia, losses of particular interneuron populations were reported. We hypothesize that the origin of GABAergic cell loss is in the mispositioning of neurons during the formation of the cerebral cortex. Here we report that in C57 black mice exposed to hypoxic conditions (9% O; 3% CO), 22-26% of cell loss was detected in the cortical plate as early as four days after the hypoxic event. Moreover, the surviving cells failed to populate the proper layers in the developing cortex. Differential sensitivities were observed in neurons that originated from different germinal zones. A significant effect of GABAergic cell location along the anterior-posterior and medio-lateral axes on neuron sensitivity to hypoxia was detected. Finally, changes in guidance molecules in the developing cortex, including increases in hypoxia-inducible factor 1-alpha levels and intracellular distribution, decreases in reelin levels in the cortical plate and altered organization of radial glia, were observed. These changes in the molecular landscape of the immediate environment of the immature neurons may contribute to the observed outcomes in neuronal migration to, and establishment in, the correct cortical layers. We suggest that the interneuron loss may be related to these early events.
一些与宫内环境相关的条件与晚年的神经精神疾病有关。在人类中，大约有 2%的婴儿会暴露于围产期缺氧缺血或长时间缺氧性损伤中，极低出生体重早产儿对这种情况的敏感性最高。对这些情况的一些表现的尸检组织分析将其与受影响受试者大脑中 GABA 通路功能的变化联系起来。使用早期生命缺氧缺血的动物模型，报道了特定中间神经元群体的丧失。我们假设 GABA 能神经元丧失的起源是在大脑皮层形成过程中神经元的错位。在这里，我们报告说，在 C57 黑鼠暴露于缺氧条件（9% O；3% CO）下，早在缺氧事件发生四天后，皮质板中就检测到 22-26%的细胞丧失。此外，存活的细胞未能在发育中的皮质中填充适当的层。起源于不同生殖区的神经元表现出不同的敏感性。在沿前后和中侧轴的 GABA 能细胞位置对神经元对缺氧的敏感性方面观察到显著影响。最后，发育中的皮质中导向分子的变化，包括缺氧诱导因子 1-α水平的增加和细胞内分布的改变，皮质板中 reelin 水平的降低以及放射状胶质的改变组织，被观察到。这些未成熟神经元的即时环境分子景观的变化可能导致观察到的神经元迁移到正确的皮质层并在其中建立的结果。我们认为中间神经元的丧失可能与这些早期事件有关。
