Defective Hippocampal Primary Ciliary Function and Aberrant LKB1/AMPK Signaling Pathway Are Associated With the
Ziyao Han1, Xiaoyue Yang1, Jianxiong Gui1
1Department 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, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
Insights
Advanced maternal age (AMA) in rats impairs offspring hippocampal autophagy and primary cilia development. This is linked to abnormal LKB1/AMPK pathway activation, affecting learning and memory.
Area of Science:
- Neuroscience
- Developmental Biology
- Cellular Biology
Background:
- Advanced maternal age (AMA) is linked to negative impacts on offspring development and cognitive functions.
- The precise mechanisms underlying these effects, particularly concerning hippocampal function, require further investigation.
- Autophagy and primary cilia in the hippocampus are critical for learning and memory.
Purpose of the Study:
- To investigate the effects of AMA on hippocampal autophagy and primary cilia in offspring rats.
- To explore the relationship between AMA-induced changes in the hippocampus and the LKB1/AMPK signaling pathway.
- To elucidate the molecular mechanisms linking AMA to cognitive deficits in offspring.
Main Methods:
- Offspring rats from AMA (12-month-old mothers) and control (3-month-old mothers) dams were studied at postnatal days 14, 28, and 60.
- Transmission electron microscopy was used to quantify autophagosomes.
- Quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence were employed to assess gene expression and primary cilia.
Main Results:
- Autophagic activity was significantly inhibited in offspring from AMA dams across developmental stages.
- Primary ciliogenesis and growth in the hippocampus were impaired in AMA offspring, with astrocytes showing more severe effects.
- The LKB1/AMPK signaling pathway was abnormally activated in the AMA group.
Conclusions:
- AMA negatively impacts hippocampal autophagy and primary cilia development in offspring rats.
- Aberrant activation of the LKB1/AMPK signaling pathway is associated with these impairments.
- These molecular and cellular changes likely contribute to the cognitive deficits observed in offspring of advanced maternal age.
Abstract:
Advanced maternal age (AMA) negatively influences the development and cognitive functions of offspring. However, the underlying mechanism remains to be elucidated. As hippocampal autophagy and primary cilia play a crucial role in learning and memory abilities, this study aimed to investigate the effects of AMA on hippocampal autophagy and primary cilia, and to explore their relationship with the changes of LKB1/AMPK signaling pathway in offspring rats. The whole brains and hippocampus of offspring born to 12-month-old (AMA) and 3-month-old (control) Sprague-Dawley (SD) female rats were collected on post-natal days (P) 14, 28, and 60. Transmission electron microscopy was employed to count the number of autophagosomes. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to quantify gene expression, and immunofluorescence was used to measure primary cilia. The results revealed that autophagic activity was inhibited from childhood to adulthood in the AMA group. Furthermore, in the early developmental stage, primary ciliogenesis and growth in the hippocampus in the AMA group were impaired, with astrocytes being more severely affected. In addition, the AMA group exhibited an abnormal activation of the LKB1/AMPK signaling pathway. Thus, in offspring born to mothers of AMA, impaired hippocampal primary ciliary function and aberrant activation of the LKB1/AMPK signaling pathway are associated with inhibited autophagic activity.
