Rodriguez-Duboc A, Basille-Dugay M, Debonne A, Rivière M-A, Vaudry D, Burel D
Univ Rouen Normandie, Inserm, U1245, Normandie Univ, F-76000, Rouen, France.
Univ Rouen Normandie, Inserm, U1239, Normandie Univ, F-76000, Rouen, France.
Curr Res Neurobiol. 2023 Oct 20;5:100113. doi: 10.1016/j.crneur.2023.100113. eCollection 2023.
Apnea of prematurity (AOP) affects more than 50% of preterm infants and leads to perinatal intermittent hypoxia (IH) which is a major cause of morbimortality worldwide. At birth, the human cerebellar cortex is still immature, making it vulnerable to perinatal events. Additionally, studies have shown a correlation between cerebellar functions and the deficits observed in children who have experienced AOP. Yet, the cerebellar alterations underpinning this link remain poorly understood. To gain insight into the involvement of the cerebellum in perinatal hypoxia-related consequences, we developed a mouse model of AOP. Our previous research has revealed that IH induces oxidative stress in the developing cerebellum, as evidenced by the over-expression of genes involved in reactive oxygen species production and the under-expression of genes encoding antioxidant enzymes. These changes suggest a failure of the defense system against oxidative stress and could be responsible for neuronal death in the cerebellum. Building upon these findings, we conducted a transcriptomic study of the genes involved in the processes that occur during cerebellar development. Using real-time PCR, we analyzed the expression of these genes at different developmental stages and in various cell types. This enabled us to pinpoint a timeframe of vulnerability at P8, which represents the age with the highest number of downregulated genes in the cerebellum. Furthermore, we discovered that our IH protocol affects several molecular pathways, including proliferation, migration, and differentiation. This indicates that IH can impact the development of different cell types, potentially contributing to the histological and behavioral deficits observed in this model. Overall, our data strongly suggest that the cerebellum is highly sensitive to IH, and provide valuable insights into the cellular and molecular mechanisms underlying AOP. In the long term, these findings may contribute to the identification of novel therapeutic targets for improving the clinical management of this prevalent pathology.
早产呼吸暂停（AOP）影响超过50%的早产儿，并导致围产期间歇性缺氧（IH），这是全球范围内发病和死亡的主要原因。出生时，人类小脑皮质仍未成熟，使其易受围产期事件影响。此外，研究表明小脑功能与经历过AOP的儿童所观察到的缺陷之间存在关联。然而，支撑这种联系的小脑改变仍知之甚少。为了深入了解小脑在围产期缺氧相关后果中的作用，我们建立了AOP小鼠模型。我们之前的研究表明，IH在发育中的小脑中诱导氧化应激，参与活性氧生成的基因过度表达以及编码抗氧化酶的基因表达不足证明了这一点。这些变化表明抗氧化应激防御系统失效，可能是小脑神经元死亡的原因。基于这些发现，我们对小脑发育过程中涉及的基因进行了转录组学研究。使用实时PCR，我们分析了这些基因在不同发育阶段和各种细胞类型中的表达。这使我们能够确定P8时的脆弱时间框架，P8代表小脑中下调基因数量最多的年龄。此外，我们发现我们的IH方案影响了几个分子途径，包括增殖、迁移和分化。这表明IH可以影响不同细胞类型的发育，可能导致该模型中观察到的组织学和行为缺陷。总体而言，我们的数据强烈表明小脑对IH高度敏感，并为AOP潜在的细胞和分子机制提供了有价值的见解。从长远来看，这些发现可能有助于确定新的治疗靶点，以改善这种常见疾病的临床管理。
