Han Wei, Pan Ya'nan, Han Ziyao, Cheng Li, Jiang Li
Department of Neurology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
Front Pediatr. 2022 Mar 3;10:850213. doi: 10.3389/fped.2022.850213. eCollection 2022.
The effects of advanced maternal age (AMA) on the neurodevelopment of offspring are becoming increasingly important. Myelination is an important aspect of brain development; however, a limited number of studies have focused on the effects of AMA on myelination in offspring. The current study aims to evaluate the association between AMA and myelin sheath development in offspring. We studied the learning and memory function of immature offspring using the novel object recognition test. Then, we investigated the expression of myelin basic protein (MBP) in the immature offspring of young (3-month-old) and old (12-month-old) female rats at different time points (14, 28, and 60 days) after birth with immunofluorescence and western blotting. The myelin sheath ultrastructure was observed with transmission electron microscopy in immature and mature offspring. Extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2) were investigated by western blot in immature offspring at the above time points. AMA impaired the memory function of offspring during early postnatal days. The MBP expression level gradually increased with postnatal development in the offspring of both the AMA and Control (Ctl) groups, but the MBP level in the offspring of the AMA group was lower than that of the Ctl group at 14 days after birth. In addition, the ultrastructure of the myelin sheath was defective in AMA offspring during the early postnatal period; however, the myelin sheath was not significantly affected in offspring during adulthood. Interestingly, ERK phosphorylation at 14 days after birth was lower in AMA offspring than in Ctl offspring. However, ERK phosphorylation at 28 days after birth was higher in AMA offspring than in Ctl offspring. The peak of ERK phosphorylation in the AMA group was abnormal and delayed. Our results indicated that AMA is associated with poor developmental myelin formation in offspring. The ERK signaling pathway may play an essential role in the adverse effects of AMA on the offspring myelin sheath development.
高龄产妇（AMA）对后代神经发育的影响日益受到关注。髓鞘形成是大脑发育的重要方面；然而，仅有少数研究关注了AMA对后代髓鞘形成的影响。本研究旨在评估AMA与后代髓鞘发育之间的关联。我们使用新物体识别测试研究了未成熟后代的学习和记忆功能。然后，我们通过免疫荧光和蛋白质印迹法，在出生后不同时间点（14、28和60天），研究了年轻（3个月大）和年老（12个月大）雌性大鼠未成熟后代中髓鞘碱性蛋白（MBP）的表达。通过透射电子显微镜观察未成熟和成熟后代的髓鞘超微结构。在上述时间点，通过蛋白质印迹法研究未成熟后代中的细胞外信号调节激酶1和2（ERK1/2）以及磷酸化ERK1/2（p-ERK1/2）。AMA损害了产后早期后代的记忆功能。AMA组和对照组（Ctl）后代的MBP表达水平均随出生后发育逐渐升高，但出生后14天，AMA组后代的MBP水平低于Ctl组。此外，AMA后代在产后早期髓鞘超微结构存在缺陷；然而，成年后代的髓鞘未受到显著影响。有趣的是，出生后14天，AMA后代的ERK磷酸化水平低于Ctl后代。然而，出生后28天，AMA后代的ERK磷酸化水平高于Ctl后代。AMA组ERK磷酸化的峰值异常且延迟。我们的结果表明，AMA与后代发育性髓鞘形成不良有关。ERK信号通路可能在AMA对后代髓鞘发育的不利影响中起重要作用。
